key: cord-0749283-g8jk9zxv
authors: Alfaleh, Mohamed A.; Alsaab, Hashem O.; Mahmoud, Ahmad Bakur; Alkayyal, Almohanad A.; Jones, Martina L.; Mahler, Stephen M.; Hashem, Anwar M.
title: Phage Display Derived Monoclonal Antibodies: From Bench to Bedside
date: 2020-08-28
journal: Front Immunol
DOI: 10.3389/fimmu.2020.01986
sha: ed25c2f8a78e69edf424befa586af735e44e325e
doc_id: 749283
cord_uid: g8jk9zxv

Monoclonal antibodies (mAbs) have become one of the most important classes of biopharmaceutical products, and they continue to dominate the universe of biopharmaceutical markets in terms of approval and sales. They are the most profitable single product class, where they represent six of the top ten selling drugs. At the beginning of the 1990s, an in vitro antibody selection technology known as antibody phage display was developed by John McCafferty and Sir. Gregory Winter that enabled the discovery of human antibodies for diverse applications, particularly antibody-based drugs. They created combinatorial antibody libraries on filamentous phage to be utilized for generating antigen specific antibodies in a matter of weeks. Since then, more than 70 phage–derived antibodies entered clinical studies and 14 of them have been approved. These antibodies are indicated for cancer, and non-cancer medical conditions, such as inflammatory, optical, infectious, or immunological diseases. This review will illustrate the utility of phage display as a powerful platform for therapeutic antibodies discovery and describe in detail all the approved mAbs derived from phage display.

They also have a high success rate in clinical development; for instance, it has been reported that the probability of FDA approval for mAbs in phase I of development is ∼14.1%, which is almost twice the approval rate of small molecule drugs (∼7.6%) (10, 11) . Such factors make biopharmaceutical companies more motivated and willing to sponsor the development of these pharmaceutical products.

During the last 120 years, the research and development of antibody-related technologies have been the subject of four Nobel Prizes. In 1901, Emil von Behring won the first Nobel Prize in Physiology or Medicine for the successful therapeutic use of horse hyperimmune serum containing neutralizing polyclonal antibodies against diphtheria and tetanus toxins (12) . Kohler and Milstein received the 1984 Nobel Prize in Physiology or Medicine for developing the ground-breaking hybridoma technology which facilitated the isolation of mAbs and their subsequent production in laboratories (13) . In 2018, George P. Smith and Sir Gregory P. Winter were awarded with the Nobel Prize in Chemistry for their development of phage display of peptide and antibodies (14-16). In the same year, James P. Allison and Tasuku Honjo were honored by the 2018 Nobel Prize in Physiology or Medicine for their discoveries of cancer immunotherapy via the use of antibody blockade of the T-cell inhibitory receptor (CTLA-4) and programmed cell death protein 1 (PD1) to enhance anti-tumor immune responses (17, 18) .

Although hybridoma technology was ground-breaking at the time and still commonly used to produce antibodies as research reagents, murine-derived mAbs have limited therapeutic efficacy. Several reports have indicated that patients treated with murine-derived mAbs will develop a human antimouse antibody (HAMA) response, which accelerates mAb clearance, and could result in undesirable allergic reactions upon repeated administration (19, 20) . Antibody engineering techniques have been subsequently utilized to create chimeric or humanized antibodies by utilizing the murine variable regions or complementary determining regions (CDRs), respectively, in conjunction with human constant regions, in order to maintain target specificity and reduce the HAMA response (21) (22) (23) . Fully human antibodies are now generated using hybridoma technology in transgenic mice models, such as HuMabMouse and XenoMouse, whereby the mouse immunoglobulin (Ig) gene loci have been replaced with human loci within the transgenic mouse genome (24) (25) (26) .

Development of antibody phage display libraries represents an alternative technique to the traditional hybridoma technology. They involve the isolation of fully human-derived mAbs from large Ig gene repertoires displayed on the surface of bacteriophages (16) . In 1985, George P. Smith was the first FIGURE 2 | Strategy used for construction of naïve scFv-phage display libraries. Total RNA is isolated from B-lymphocytes from non-immunized healthy donors. Then cDNA is synthesized from the isolated RNA using reverse transcriptase enzyme. Then the repertoire of the V H and V L genes is amplified from the cDNA using forward and reverse primers hybridizing to the variable domains. scFvs are constructed and cloned into phagemid vector and a naïve phage library of 10 8 -10 10 is usually generated.

to describe phage display technology by demonstrating that filamentous phages are able to display a peptide of interest on their surfaces after inserting a foreign DNA fragment into the filamentous phage coat protein gene (14) . Subsequently, Parmley and Smith described a selection and affinity enrichment process known as "panning or biopanning, " that allowed for the isolation of peptide-phage fusions from a 10 8 -fold excess of wild type phages based on their specific binding affinity to biotinylated antibodies specific for the peptides (27). Later, McCafferty and Winter were the first to utilize phage display technology in antibody discovery by creating combinatorial antibody libraries on filamentous phages to be utilized for generating antigen specific mAbs (15, 16) .

M13 is one of the filamentous bacteriophages (Ff) of Escherichia coli (E. coli), and one of the most widely used phages for antibody phage display (28, 29) . Filamentous bacteriophages only infect E. coli strains through an interaction between the expressed F pilus on the surface of hosts, and a phage coat protein (30). M13 is a flexible cylindrical-shaped virus particle containing a circular single-stranded DNA genome (6,407-base) consisting of nine genes encoding for five coat proteins (pIII, pVIII, pVI, pVII, and pIX), and six assembly and replication proteins (31, 32). Most major phage display systems are based on pIII-antibody fusion proteins, due to pIII structural flexibility and its ability to display large proteins without losing its function (33-36).

The discovery of smaller recombinant antibody formats, such as variable domain [Fv; variable regions of the heavy (V H ) or light chain (V L )], single-chain variable domain (scFv), diabodies (bivalent scFvs), heavy-domain camelid and shark antibody fragments (VHHs, nanobodies), and fragment antigen binding (Fab), has helped to advance antibody phage display technology (Figure 1 ) (37-42). These smaller fragments are more amenable to expression in bacteria compared to full antibodies, which require assembly of four polypeptide chains and extensive disulfide bond formation. For instance, creating a combinatorial scFv library on the surface of M13 filamentous phage has been achieved through combining populations of V H and V Ldomains, which are joined by a flexible, protease resistance glycine-serine linker (Gly 4 Ser) 3 , into a single DNA sequence (15) . These antibody sequences are then introduced and cloned as a gene fusion with the bacteriophage pIII gene under the control of a weak promoter in a phagemid vector; a plasmid that carries an antibiotic resistance gene, bacterial and phage origins of replication (Figure 2 ) (43-46).

Co-infection of E. coli harboring a phagemid with a helper phage is essential for the formation of functional phage particles displaying pIII-antibody fusions (45). It causes E. coli to initiate the synthesis of all wild-type coat proteins needed for phage replication, and this is essential because the phagemid does not have all the genes necessary to encode a full bacteriophage in E. coli (47). The most commonly used helper phage is M13KO7, which is a derivative of M13 containing a kanamycin resistance gene and the P15A origin of replication that allows the genome to replicate as a plasmid in E. coli (48). A fully assembled phage particle contains five copies of the pIII protein, but since the wild type pIII gene from helper phage has superior expression levels compared to the phagemid-encoded pIII-antibody fusion gene, the majority of the produced phage population is expressed without a pIII-antibody fusion. However, only a portion of the population will contain monovalent display of the pIII-antibody fusion, with polyvalent display being much less frequent (49). The hyperphage system, which uses a helper phage lacking the pIII gene has been utilized for antibody pIII-antibody polyvalent display, because only the pIII-antibody gene of the phagemid is encoded (50). Nevertheless, monovalent display is the most FIGURE 3 | Schematic representation of phage biopanning. This is the basic method for sequential affinity screening of the phage display libraries for specific binding phage from a large excess of non-binding clones is often referred to as "panning or biopanning." The phage antibody selection involves the immobilization of the ligand of interest on a solid support, followed by applying the phage display library (in the form of purified virions) to the immobilized ligand to allow binding of specific variants. To eliminate the adherent non-binders, multiple rounds of washing are usually performed, and remaining bound phages are eluted and re-amplified. At least three rounds of biopanning are usually required in order to amplify the binding variants and to exclude any non-specific binders.

popular display system because it allows for selection of higher affinity antibodies, avoiding the avidity effect of polyvalent display (43-46).

When purified antigens are available, they can be presented to a phage antibody library by immobilization on solid surfaces, such as nitrocellulose membranes, polystyrene tubes or plates, magnetic beads or column matrices (51-53). The use of blocking agents, such bovine serum albumin (BSA), milk or casein can block the remaining sites present on the solid surface to prevent non-specific phage binding to the surface (54, 55). After the phage library is exposed to the immobilized antigens, unbound phages are usually washed away (Figure 3) . Such washing step is critical to remove non-specific binders, and to allow for some control over binding properties by manipulating the wash buffer and stringency of washing. For example, long wash times can be incorporated to ensure only clones with slow dissociation rates are selected. Detergents are usually included in wash buffers, but they can also be altered for factors, such as pH and salt concentration. The washing steps are gradually increased with every round of biopanning to increase the stringency in order to isolate higher affinity phage clones (46, 56).

To recover high-affinity phage antibodies from immobilized antigens, different elution conditions, including change in pH, proteolytic cleavage or competition with free antigens have been used. For pH elution, either acidic buffers, such as glycine or citric acid (52, 57), or alkaline triethylamine (TEA) can be used (51). It is crucial to neutralize the pH of eluted phage antibodies to be around 8, to avoid degradation of the phage and maintain infectivity. Some libraries have a cleavage site introduced between the antibody and the pIII protein to facilitate elution by using proteases, such as Genenase I or trypsin (58, 59).

After several rounds of biopanning, the pool of phages isolated from each round is tested, usually by ELISA, to determine if there is an enrichment of phage binders toward the specific antigen within the polyclonal pool. The polyclonal ELISA involves immobilizing antigen onto microtitre plates, followed by addition of various dilutions of the phage pool from each round and then detection of bound phage using an anti-M13 phage antibody. Individual clones from the round of biopanning exhibiting the maximum enrichment level are then further screened by ELISA to determine individual phage isolates with high specificity toward the antigen of interest. The procedure involves growing single colonies cell glycerol stock from the last performed biopanning round in a 96-well plate format, before adding the helper phage to induce production of phage particles. The positive clones derived from this experiment can then be analyzed by restriction fragment length polymorphism to determine the number of unique clones, or by sequencing which also determines the CDRs for both heavy and light chains (60). Once positive clones are isolated, downstream applications would determine how they are further processed. For example, a scFv gene from a phage clone can be re-cloned into a bacterial expression vector for large scale production or reformatted into a full mAb by inserting the variable regions into expression vectors containing the antibody constant regions (61). In vitro affinity maturation using mutated libraries of lead phage clones can also be conducted in order to increase the affinity and the stability of the selected antibodies (62, 63).

Although biopanning of immobilized antigen on solid surfaces is robust, it is often limited by the availability of purified protein and the possibility of its altered conformation when attached to solid surfaces. Therefore, alternative methods, such as in-solution biopanning, followed by affinity capture of antigens tagged with biotin (64), or calmodulin binding peptide have been used (65).

Some membrane proteins (66) are poorly soluble in an aqueous media, and due to their complexity, they do not form properly during recombinant expression (67). They might form aggregates and lose their tertiary structures when coated on immunotubes before biopanning (68-70), which as a result might lead to generate antibody binders that recognize epitopes that are not naturally exposed (71, 72) . Thus, cell-based biopanning is often utilized to maintain membrane proteins native conformation (73) (74) (75) (76) . It can be applied to retrieve antibodies that are specific for either known or unknown antigens on cells surface, and it can be performed in case of unavailability of the targeted antigen in pure form (77) (78) (79) (80) . Furthermore, cell-based biopanning strategies allow for selecting binders to a specific conformational state of a cell surface receptor (81) (82) (83) (84) (85) . Cell-based microselection approach, can be applied to retrieve unique binders, and identify novel biomarkers that are exclusively expressed on rare cells within a heterogeneous solution (86, 87) .

The latest advancements in next-generation sequencing (NGS) technologies, bioinformatics and nanotechnology have tremendously improved the high-throughput screening of antibody discovery (88) (89) (90) (91) . For instance, a report from Raftery et al. (92) described a rapid selection of scFv-phage (PhageXpress) using electrohydrodynamic-manipulation of a solution containing phage library particles in combined with Oxford Nanopore Technologies' MinION sequencer. After a single round of biopanning and within 2 days compared to several weeks if applying traditional biopanning, they were able to identify 14 anti-dengue virus non-structural protein 1 scFv. Adopting similar approaches will significantly reduce the time and amount of laborious lab work required to discover putative antibodies, which are major obstacles in the traditional biopanning method, and will help accelerate developing therapeutic monoclonal antibodies during emerging infectious outbreaks (93) .

Antibody phage display is a versatile, in vitro selection technology that can be utilized to discover high affinity antibodies specific to a wide variety of antigens (94) . However, specificity and high affinity are not the only attributes that account for successful therapeutic antibodies. Other antibody quality attributes, such as solubility, viscosity, expression yield, and thermal and long-term stability are vital to ensure the success of mAb lead candidates in biomanufacturing and clinical trials (95, 96) . These biophysical properties of antibodies are strongly dependent on their amino acid sequences (97) . Some mAbs might have poor developability profiles because of high immunogenicity, physicochemical instability, self-association, high viscosity, poly-specificity, short half-life, and poor expression (98, 99) . For instance, low solubility can lead to issues during biomanufacturing (100) (101) (102) , and could affect mAb potency, bioavailability and immunogenicity (103, 104) . High thermal stability is crucial to maintain structural and functional integrity, and intrinsic properties, under different temperatures (105, 106) . Furthermore, aggregation is one of the main challenges that limit the advancement of therapeutic mAb due to immunogenicity concerns (107) (108) (109) (110) .

Despite the several advantages of antibody phage display, such as bypassing animal immunization, the ability to isolate antibodies against toxic or non-immunogenic antigens and the ability to generate conformation-specific antibodies, the vast majority of the approved therapeutic antibodies are derived from immunized mice technologies. This is because the filtration process that imposed by the immune system enables mammalians derived antibodies to have better biophysical attributes compared to antibodies generated by phage display (111). In agreement with this, Jain et al. has comprehensively analyzed the biophysical attributes for 46 FDA approved therapeutic antibodies and 89 in advance clinical trials (96) . They found that antibodies directly discovered by phage display or engineered at some point by phage biopanning exhibit significant developability risks' properties compared to than those derived from immunized mice. Further investigations found that phage display derived therapeutic antibodies have higher self-interaction and poly-reactivity due to the higher percentage of aliphatic residues in their CDRs compared to the non-phage derived antibodies (112).

Additionally, antibodies selected form phage display libraries are not glycosylated, because they are produced in E. coli, as a result, some candidates when glycosylation occur during mammalian cells expression; their binding, biodistribution, or pharmacokinetics might be negatively impacted (113-116). Therefore, using eukaryotic display platforms like yeast and mammalian display would be beneficial. For instance, in addition to their ability to produce glycosylated proteins, yeast and mammalian antibody libraries can be constructed to display fulllength antibodies as well as antibody fragments, such as scFvs and fragment antigen-binding region (Fabs) (117-126), allowing the isolation of high affinity antibodies with definitive biological characteristics (122, 123). For example, Parthiban et al. has developed mammalian libraries that display around 10 million clones in IgG-format on the surface of HEK293 cells using CRISPR/Cas9 or transcription activator-like effector nucleases (TALENs) (127). These libraries can act as a quality filter for different antibody developability aspects, and to provide a very early insight into developability problems, such as aggregation and cross-reactivity. Each display system has its advantages and disadvantages, however, determining those are beyond the intended scope of this review, which is about the most commonly used type of antibody display, the phage display. Therefore, it is vital to generate phage libraries that allow for the isolation of highly specific and diverse mAbs with high affinity against diverse antigens with optimal developability potential (128-130).

Currently, as a common practice in industrial pipelines, biopharmaceutical companies are implementing extensive developability assessments to determine the biochemical and biophysical features of antibody candidates to help identifying candidates with more favorable biophysical properties and to avoid difficulties during the downstream process (131, 132). For example, in silico platforms, such as the Therapeutic Antibody Profiler (TAP) tool are used as a flagging system to predict mAbs with poor developability profiles by identifying anomalous values compared with therapeutic mAbs in clinical-stages. Indeed, features within the variable regions of mAbs, such as the total CDRs length, high hydrophobicity of V H and V L chains, lack of net charge symmetry, and/or the presence of patches of positive and negative charges were computationally predicted to be key factors in developability profiles of mAbs (133).

The probability of isolating high affinity, and more diverse mAbs that specifically bind random epitopes, increases significantly when biopanning campaigns are performed using larger antibody libraries. Library diversity is judged by how many functional antibody fragments are able to identify as many different antigens as possible (134). The bacterial transformation step during library construction; however, is a main practical bottleneck that limits the size of the library from exceeding 10 11 antibody variants, even after optimization and performing numerous electroporation steps.

Ideally, antibody phage display libraries should not only be large and diverse, but also should display antibody variants as functional fragments. Issues related to the nucleotide sequences, such as the presence of stop codons, or the addition/deletion of nucleotides can occur during the library construction (135-137). These issues might inhibit the production of functional pIII-antibody fusions or change the reading frame of the antibody gene sequence, which could negatively affect their biophysical characteristics. Some in-frame antibody genes might also have poor expression levels from their phagemid, or produce aggregated, misfolded, or toxic antibody fragment to E. coli (138-141). However, such variants are usually displayed in lower percentage compared to other variants or phages that do not display any fusion protein.

Phage libraries generated from human rearranged V-gene repertoires are constructed from mRNA or RNA extracted from B cells of immunized or naïve donors (Figure 2 ) (73, (142) (143) (144) . Construction of immunized or naïve libraries involves using reverse transcription polymerase chain reaction (RT-PCR) to prepare the cDNA template. This is followed by the amplification of the repertoire of V L and V H genes by PCR, before cloning into the phagemid.

Immunized libraries are constructed from lymphoid tissues of individuals who carry a particular disease, such as metastatic cancer or particular infection, or have been immunized with a particular antigen (145-149). Such libraries are characterized by a biased antibody repertoire toward specific targets. Additionally, those antibodies tend to have much higher affinities for the desired antigen than antibodies isolated from naïve libraries of comparable size, because the V H and V L gene fragments have undergone the natural in vivo affinity maturation process (150) . Naïve libraries, on the other hand, represent the germline diversity of antibody repertoire. These libraries are generated from healthy donor's mRNA or RNA without bias toward a particular disease state, and are used to yield mAbs against unlimited range of antigens (151) . To generate a highly diverse naïve antibody phage library, it is recommended to use a large pool of donors from diverse ethnic groups, and to maximize the efficiency of antibody gene amplification in the process of library construction (152) (153) (154) (155) .

The CDRs play a significant role in antigen recognition (156) , although some of the non-CDRs residues contribute to the antibody-antigen interaction (157) . Each CDR loop contributes differently to antibody-antigen binding, and each residue within each CDR loop plays a different role in this interaction (158, 159) . Among all the six CDR loops, the V H CDRs, especially V H 's CDR3 (CDRH3), are more frequently involved in the antigen binding than those in the light chain (160, 161) . The CDRH3 loop, which exists in a variety of different lengths (5-30 amino acids), is of particular importance due to its substantial impact on the canonical conformation and antigen binding compared to the other CDRs (156, (162) (163) (164) (165) . Noteworthy, the loop length of CDRH3 does not only affect the specificity and affinity of the antibody for its specific antigen, but also affects the nature of the binding of other CDRs. Specifically, for antibodies with long CDRH3 loops, these loops are responsible for most of the antibody-antigen interactions, while in antibodies with short CDRH3 loops, other CDRs loops usually assist in antigen binding (156) . Thus, CDRH3 plays a major role in recognizing diverse targets, and generating interactions with acceptable affinity (166, 167) .

The diversity of the V-gene segments can be designed and synthesized artificially by CDRs randomization. These libraries can be fully synthetic or semisynthetic. Synthetic libraries are made to maximize antibodies' functionality by making a large and highly diverse phage repertoire. This is usually achieved in vitro by using PCR and oligonucleotides to create a random integration of the CDRs as well as introduction of different CDRH3 loop sequences and lengths without disrupting the folding of the V regions (94, 168) . Semisynthetic libraries combine natural and synthetic antibody diversity. They are constructed from non-rearranged Vgenes from pre-B cells, or an antibody framework with randomization of the CDRH3 or several CDRs utilizing degenerated oligonucleotides (128, 169, 170) .

Data collected for this review were obtained from different sources including PubMed, the clinical trial database (www. clinicaltrials.gov), patents, company websites, and international ImMunoGeneTics information system (www.imgt.org). A CAT, Cambridge Antibody Technology human antibody phage display library; HuCAL, Human combinatorial antibody library; PBL, Bone marrow, peripheral blood lymphocytes; TRIM, trinucleotide-directed mutagenesis method. selection of phage display-derived therapeutics was described in great detail previously (171, 172 ), yet we here present an updated and comprehensive review of phage display-derived mAbs. Two decades after McCafferty and Winter's seminal report in 1990, more than 70 phage-derived mAbs entered clinical studies, and 14 of them have been approved. The majority of these antibodies are generated by three company-owned libraries, Cambridge Antibody Technology (CAT), Dyax and MorphoSys's human combinatorial antibody libraries (HuCAL R ) (Table 1, Figure 4 ). MorphoSys's HuCAL R has the highest number of mAbs (20 mAbs), wherein 19 are under clinical development, and one (Tremfya TM ) is approved. The majority of the MorphoSys's HuCAL R derived mAbs (12 mAbs) are in phase II clinical trials. CAT (AstraZenica) has the second highest number of phage derived mAbs (15 mAbs) in clinical trials, and the highest number of approved mAbs including Humira R , Benlysta R , Lumoxiti TM , ABthrax R , and Gamifant R . Dyax has 13 mAbs in which four of them have been approved; Bavencio R , Portrazza TM , Cyramza R , Takhzyro R .

Therapeutic mAbs from phage libraries can be successfully isolated to treat cancer, and non-cancer medical conditions, such as inflammatory, optical, infectious, or immunological diseases ( Table 2) . However, some of the aforementioned major libraries have a favorable therapeutic area of application. More mAbs for non-cancer indications in comparison to cancer indications (∼63 vs. ∼37%) were developed using CAT libraries. Among all the five approved CAT derived mAbs, Lumoxiti TM is the only one that is indicated to treat cancer. Unlike CAT, Dyax libraries have Frontiers in Immunology | www.frontiersin.org been remarkably useful in the development of therapeutic mAbs for oncology at the expense of non-oncology indications (∼70 vs. ∼30%), in which three out of the four approved mAbs are anti-cancer agents ( Figure 5 ). MorphoSys's HuCAL R libraries have almost equally contributed to both cancer and non-cancer indications ( Figure 5) . The most dominant antibody format of the approved or under clinical investigations phage-derived antibodies is the Immunoglobulin G (IgG), yet other formats, such as antibody conjugates or nanobodies are also included ( Table 2) . MAbs isolated from the CAT libraries, for instance, belong to two IgG subclasses, IgG1 and IgG4, with the majority being IgG1λ. MorphoSys's HuCAL R platforms show similar trend to CAT in addition to large number of mAbs from IgG2 subclass. MAbs from Dyax libraries, on the other hand, belong to IgG1 and IgG2 with the majority being IgG1-κ.

Having more than one mAb against a specific target or condition is essential especially that patients might acquire resistance against a prescribed therapeutic mAb, because of the possible immunogenicity and induction of anti-drug antibodies (ADAs) (459, 460) . As a result, their pharmacokinetic, safety, and efficacy can be negatively impacted by the presence of ADAs (459) (460) (461) . From this perspective, antibody phage display technology has enabled receptors like mesothelin (MSLN), human epidermal growth factor receptor 3 (HER3) and programmed cell death-ligand 1 (PD-L1) to have more than one specific therapeutic mAb ( Table 2) .

As discussed earlier, phage display technology demonstrated its robustness and reproducibility as a human antibodies discovery platform. To date, 14 approved mAbs and many others in preclinical development or in clinical trials have been derived using this technology. These antibodies and antibody fragments are indicated to treat several disease conditions ( Table 2) . In this section, we will discuss in detail all the approved phage displayderived antibodies to highlight the utility of antibody phage display technology in the universe of biopharmaceutical industry.

Atezolizumab is a humanized IgG1-κ immune checkpoint inhibitor targets PD-L1 that commonly expressed on the surface of antigen presenting cells and tumor cells, and prevents its binding to the programmed cell death protein 1 (PD-1) receptor on T cells. PD-L1 is usually released by tumor cells and results in cancer immune evasion and decreases antitumor T-cell responses which are usually associated with poor clinical outcomes. Thus, utilizing atezolizumab could disrupt such T cell suppression by blocking PD-L1 binding to PD-1 and restore tumor-specific T-cell immunity in several cancer types (462) (463) (464) (465) (466) (467) (468) (469) (470) (471) (472) (473) .

In 2016, atezolizumab was approved by the US FDA for the treatment of urothelial carcinoma (UC) and metastatic lung cancer. Subsequently, it was granted accelerated approval for the treatment of advanced bladder cancer in 2017, and metastatic non-small-cell lung carcinoma (NSCLC) in combination with bevacizumab and chemotherapy in 2018. More recently, atezolizumab was approved for several indications, such as in combination with abraxane for patients with PD-L1-positive metastatic triple-negative breast cancer (PD-L1-positive TNBC), in combination with chemotherapy for the initial treatment of adults with extensive-stage small-cell lung carcinoma (SCLC), and in combination with abraxane and carboplatin for the initial treatment of metastatic non-squamous NSCLC ( Table 2) .

Clinical trials with atezolizumab are currently ongoing for multiple forms of solid tumors and hematologic malignancies. As of 2019, there are 249 ongoing trials with atezolizumab either as monotherapy or in combination with other anti-cancer agents. Ongoing clinical studies include several indications, such as NSCLC, UC, renal cell carcinoma (RCC), hepatocellular carcinoma, TNBC, colorectal cancer, and hematologic malignancies among other tumor types. Atezolizumab as a single treatment has shown a significant anti-tumor response in NSCLC (469, (474) (475) (476) , UC (466, 477) , glioblastoma multiforme (478) , and RCC (479) . In a randomized Phase II clinical trial for NSCLC, atezolizumab single treatment has shown an overall survival benefit compared to docetaxel (469) .

Avelumab is a fully human IgG1-λ immune checkpoint inhibitor that targets PD-L1 protein and blocks its interaction with PD-1. Additionally, avelumab is thought to engage the innate immune system and elicits an antibody-dependent cellular cytotoxic (ADCC) response against PD-L1-expressing tumors (480) . While ADCC has not been indicated to contribute to the clinical activity of avelumab (472) , preclinical studies suggest a possible role of ADCC in the activity of avelumab (481, 482) .

In early 2017, Avelumab was approved for metastatic Merkel cell carcinoma (mMCC) in adults and pediatric patients aged >12 years as the first approved medication for this indication in the USA (483) . In Europe, the application of avelumab marketing authorization for the treatment of mMCC is under regulatory review, while in Australia, Japan, and Switzerland phase II trial has been initiated for mMCC (483) .

In 2017, the US FDA approved avelumab in the treatment of locally advanced or metastatic urothelial carcinoma metastatic urothelial carcinoma based on the phase III JAVELIN Bladder 100 trial (NCT02603432). Additionally, in 2019 the US FDA approved avelumab for the treatment of advanced RCC in combination with the tyrosine kinase inhibitor, axitinib. The approval was based on the phase III JAVELIN Renal 101 trial (NCT02684006).

Avelumab is under phase III trial in several countries for breast cancer, head and neck cancer, NSCLC, ovarian cancer, B cell lymphoma, and gastric cancer. There are many other phase II clinical trials underway globally for glioblastoma, intestinal cancer, nasopharyngeal cancer, endometrial cancer, recurrent respiratory papillomatosis, and thymoma (483) .

Moxetumomab pasudotox-tdfk (CAT-8015) is a novel recombinant immunotoxin that consists of a recombinant murine scFv genetically fused to a truncated pseudomonas exotoxin (PE38), which targets CD22 antigen that is expressed on the surface of many types of malignant B cells including hairy cell leukemia (HCL) (263, 484) . This mAb is the second generation of BL22/CAT-3888, whereby the CDRH3 has been affinity matured by phage display to increase the affinity by 14-fold toward CD22 (485, 486) . After binding to CD22, moxetumomab pasudotox-tdfk is internalized, and the Pseudomonas exotoxin catalyzes inhibition of protein synthesis by ADP-ribosylation of elongation factor 2, resulting in apoptotic cell death (263) .

HCL is a rare chronic disease that accounts for 2% of all leukemias with a 4:1 male-to-female predominance (487, 488) . Outcomes with standard treatment are usually positive in 78% of patients however, relapses occur in ∼50% of the patients (489) . In 2018, the US FDA approved moxetumomab pasudotoxtdfk under the trade name of Lumoxiti TM (AstraZeneca Pharmaceuticals LP) to be utilized therapeutically for adult patients with relapsed or refractory HCL (R/R HCL) that no longer responding to other therapies, including purine analog (263, 490) . Lumoxiti received US Orphan Drug designation and the FDA granted the application Fast Track and Priority Review designations because of the severity and rarity of the disease and was the first new therapy granted approval for HCL since cladribine in 1993.

Currently, the national cancer institute is sponsoring a phase I clinical trial to assess the safety of moxetumomab Pasudotoxtdfk in combination with rituximab in subjects with HCL or HCL variant (NCT03805932). Furthermore, an active phase III clinical trial (NCT04125290) aims to evaluate the post-marketing safety of moxetumomab pasudotox-tdfk for old patients (≥65 years), and/or patients with moderate renal impairment.

Necitumumab is a fully human IgG1-κ mAb which selectively binds the epidermal growth factor receptor (EGFR). It binds to domain III of the extracellular region of EGFR and blocks ligand binding. Necitumumab prevents the proliferation of several cancer cell lines by affecting downstream signaling of the EGFR receptor involved in cell growth and angiogenesis (270, 491) which are crucial for promoting growth and spread of cancerous cells. Specifically, it inhibits downstream signaling pathways, such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3k)/Akt activation which in turn inhibit cancer cell proliferation, differentiation, adhesion, migration and survival (492) (493) (494) . EGFR overexpression has been found in about 40-80% of lung cancer patients as well as in many other cancers including squamous NSCLC (495, 496) .

Necitumumab was firstly approved by US FDA for the treatment of metastatic squamous NSCLC combined with gemcitabine and cisplatin in 2015 (497) . Clinical trials for necitumumab were initiated in 2004 (498) , and currently, it is being tested in 6 clinical trials (NCT02496663, NCT00982111, NCT02789345, NCT00981058, NCT03944772, NCT03387111) mostly on NSCLC.

Adalimumab is the first phage display human IgG1-κ derived mAb developed by humanization with a "guided selection method" involving a mouse mAb (180) . In 2002, adalimumab was the first human antibody derived from phage display that was granted approval for therapy by US FDA ( Table 2 ) (172) . Adalimumab is the biggest selling drug worldwide with $19.1 billion in 2019 and $82.5 billion cumulatively between 2014 and 2018 (7, 8) . It shows very high specificity and subnanomolar affinity as it binds with tumor necrosis factor (TNF) and inhibits TNF receptors (TNF-R1 and -R2) binding and activation (499) . This inhibition pathway leads to a wide range of anti-inflammatory responses as TNF is a key regulator for the initiation of proinflammatory cytokine cascade which ultimately leads to cell activation, inflammation, fever, and apoptosis (500) .

Adalimumab was firstly indicated as a therapeutic option for some moderate and severe types of rheumatoid arthritis (RA) as monotherapy or in conjunction with MTX or other anti-rheumatic medications. Nowadays, adalimumab is one of the most prescribed medicines in immune- 

Raxibacumab is a human IgG1-λ human mAb that was produced from a naive human scFv phage display library licensed from Cambridge Antibody Technology (CAT) by Human Genome Sciences (HGS), which has been later acquired by GlaxoSmithKline (GSK) (331, 501) . In 2012, raxibacumab was first granted FDA approval under the trade name of Abthrax R to be indicated as a prophylaxis for the treatment of inhalational anthrax in combination with some antibiotics. Anthrax infection is caused by bacteria called Bacillus anthracis (B. anthracis) through skin abrasions, inhalation or ingestion, where its spores are usually phagocytosed by macrophages (502) . Moreover, B. anthracis is categorized as a potential biological weapon according to the US Centers for Disease Control and Prevention (CDC) (503) .

B. anthracis secretes the lethal toxin (LT) and the edema toxin (ET). The LT is formed when the lethal factor (LF) interacts with the protective antigen (PA), which a cell-binding protein, while the ET is formed by an interaction between the PA and the edema factor (EF) (504) . Raxibacumab targets the PA in B. Anthracis with high affinity to the LT (505) and acts through neutralizing PA with a nanomolar concentrations (IC 50 is ∼0.21 nm and Kd is ∼2.78 nM). The mechanism of action of raxibacumab depends on the downregulation of the cellular uptake of toxins to prevent the development of lethal complexes (332) .

Currently, in the US, raxibacumab is not only indicated for the prophylaxis of inhaled anthrax but also when alternative therapeutic options do not exist or are not suitable, such as treatment for an antibiotic-resistant strain of B. anthracis. Raxibacumab monotherapy of antibiotic-resistant B. anthracis infection suggests a benefit for up to 6 days post-exposure (NCT00639678) (506) .

Belimumab is a human IgG1-λ mAb that was discovered through a collaboration between HGS and CAT. Belimumab recognizes and binds to the soluble B lymphocyte stimulator (BLyS), preventing its interaction with its receptors (507) . BLyS is a critical factor in the selection, maturation, and survival of B cells (508) . BLyS is produced by a wide variety of cell types, including myeloid lineage cells, activated T cells, malignant B cells, and stromal cells (509) (510) (511) (512) (513) . BLyS has three receptors that are expressed predominantly on B lineage cells, and some are found on subsets of activated T cells and dendritic cells (514, 515) .

Patients with systemic lupus erythematosus (SLE) have elevated levels of BLyS, which correlate with high levels of autoantibodies and disease activity (516) . Belimumab was FDA approved in 2011 and considered as the first biological drug, immunosuppressant, approved for the treatment of SLE. Longterm belimumab treatment causes a significant reduction of most plasma cells that are responsible for autoantibodies production (517, 518) .

Belimumab is currently being tested in seven active clinical trials. These include a phase IV clinical trial to identify the side effects of belimumab when given with other SLE medications in adults with active SLE (NCT01705977). Also, in a Phase II study to evaluate the efficacy and safety of belimumab as a maintenance therapy in adults with refractory idiopathic inflammatory myositis (IIM) (NCT02347891). It is also being investigated in Phase II studies to evaluate its efficacy in combination with rituximab in adults with systemic SLE (NCT02426125) and in subjects with primary Sjogren's syndrome (NCT02631538).

Ramucirumab is a fully human IgG1-κ mAb that inhibits vascular endothelial growth factor receptor-2 (VEGFR-2), thus inhibiting downstream signaling and preventing angiogenesis within tumors (519). In the adults, VEGFR-2 is predominantly expressed on vascular endothelial cells of blood vessels (520) . Increased levels of VEGFR-2 have been detected in mammary, colorectal cancer, NSCLC, UC, and several other cancers (521) .

The FDA approved ramucirumab in 2014 for use in the second-line setting as a single-agent treatment for advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma (522) . Also, in 2014, ramucirumab was approved in combination with docetaxel, for treatment of metastatic NSCLC (523) . In 2015, it was approved for use with FOLFIRI as a second-line treatment of metastatic colorectal cancer (524) . In 2019, ramucirumab became the first FDA-approved biomarker-driven therapy in patients with hepatocellular carcinoma for people who have high levels of alpha-fetoprotein (525) .

Currently, ramucirumab is being investigated in 19 different clinical trials for several other indications including a phase II randomized trial in combination with mFOLFIRINOX in patients with advanced pancreatic cancer (NCT02581215), phase III study in combination with chemotherapy treatment in previously untreated patients with HER2-negative, unresectable, locally-recurrent, or metastatic breast cancer (NCT00703326), and phase III trial in combination with docetaxel in patients with locally advanced or unresectable or metastatic UC (NCT02426125).

Guselkumab is a human IgG1-λ mAb that neutralizes interleukin-23 (IL-23) functions (526) . IL-23 is a pleiotropic, heterodimeric cytokine, consisting of a p19 and a p40 subunits, which are primarily secreted by antigen presenting cells, such as macrophages and dendritic cells (527) . IL-23 belongs to the IL-6/IL-12 family of cytokines that have a crucial role in numerous immune responses (528) . IL-23 specifically induces Th-17 proliferation and the subsequent release of IL-17 cytokine, which triggers inflammatory and autoimmune disorders, such as psoriasis (529) . Guselkumab binds to IL-23p19 subunit with high affinity and specificity, inhibiting interaction with its receptor on the cell surface of certain immune cell subsets, most importantly on Th17 cells (529, 530) . Such activity is responsible for preventing the activation of the IL-23 receptor and the subsequent production of several proinflammatory cytokines.

Guselkumab has demonstrated safety and efficacy in several clinical trials including a phase II proof-of-concept trial, which demonstrated efficacy in all endpoints linked to health-related quality of life as well as joint signs and symptoms, and skin disease (399, 400, 531) . Patients from this study have also experienced a dramatic decrease in IL-17A, IL-17F, and Creactive protein in their serum to normal levels compared with healthy controls, highlighting the significance of suppressing the IL-23/Th17 pathway for the treatment of skin and joint disorders (531) . This encouraging trial has led to two pivotal phase III clinical trials, DISCOVER-1 (NCT03162796) and DISCOVER-2 (NCT03162796), where patients had experienced an improved joint, skin, physical function and health-related quality of life (532, 533) . In 2017, this mAb has received approval from the US FDA to treat adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy (398) and is currently being evaluated in six active clinical trials at different phases. These include the evaluation of efficacy, safety and tolerability in patients with moderate to severe HS (NCT03628924) as well as patients with chronic plaque-type psoriasis refractory to ustekinumab treatment (NCT03553823).

Lanadelumab is a fully human IgG1-κ mAb that inhibits the proteolytic activity of plasma kallikrein (PK) enzyme. PK enzyme induces the proteolysis of the coagulation factor XII and prekallikrein (pKal), and a non-enzymatic high-molecularweight kininogen (HMWK) to generate bradykinin in response to tissue injury and pathophysiological stimuli (534) (535) (536) . The increased level of bradykinin leads to angioedema episodes, an allergic skin swelling condition, through its excessive vasodilation effect (537, 538) . This syndrome is a clinical feature of patients with hereditary angioedema (HAE), in which, a mutation in the SERPING1 gene leads to a reduced expression of C1 protein that lessens its function as a bradykinin regulator (539) . Furthermore, certain mutations in the F12 gene result in the production of factor XII with increased activity leading to excessive production of bradykinin (540) .

In phase I clinical trial, lanadelumab demonstrated a favorable safety profile with a potential inhibitory effect on HMWK and a long-term prevention of HAE attacks, enabling further evaluation in a larger trial (541, 542) . Accordingly, a phase III randomized clinical trial (NCT02586805) evaluated the efficacy and safety of lanadelumab to prevent HAE attacks in patients with symptomatic HAE due to C1 inhibitor deficiency (C1-INH-HAE) disorder (403) . In this trial, 150 or 300 mg were evaluated in subcutaneous injections setting, given every 2-4 weeks over a 6-months period. The findings from this study have demonstrated the efficacy of lanadelumab in preventing HAE attacks, leading to its approval by the US FDA in 2018 for the treatment of patients with type I or II HAE. In 2018, lanadelumab has received the US FDA approval for the prevention of the angioedema attacks in patients with hereditary angioedema. Currently, it is being evaluated in two active phase III clinical trials to prevent hereditary angioedema attacks in pediatric patients as well as in adolescent and adult patients suffering from acquired angioedema (AAE) due to C1-INH deficiency (NCT04070326 and NCT04206605).

Ixekizumab is a humanized IgG4-κ mAb that targets IL-17A cytokine, which is a member of IL-17 cytokines family mainly produced by CD4-Th17 cells. Several other immune cells residing in the gut, lung and skin, including a subset of natural killer (NK) cells, Paneth cells and neutrophils also produce IL-17A in response to IL-23 cytokine stimulation (248, 543) . The main function of Th17 cells is to clear pathogens not properly handled by the Th1 or Th2 immune response (544, 545) . The infiltration of Th17 cells under the skin and excessive production of IL17A lead to the pathophysiology of psoriasis and PsA (546) . The latter is an inflammatory disease with articular, peri-articular and extra-articular features that leads to skin and joint damage, and loss of functions (547) . Several attributes lead to this condition including immunologic, genetic and environmental factors where a combination of two or more of these factors trigger the inflammatory immune response (548-551). There has been growing evidence suggesting the involvement of IL-17 signaling in PsA pathogenesis (552) , which involves a persistent activation of Th-17 cells in response to synovial or skin antigens leading to tissue destruction and joint remodeling (552) .

Several randomized clinical trials have assessed the efficacy of ixekizumab in patients with PsA achieving a primary endpoint of American College of Rheumatology 20% improvement (ACR20) (NCT01624233, NCT02349295, NCT01695239, NCT02584855). Moreover, ixekizumab has been proven to be superior to conventional rheumatic drugs as well as TNF-α inhibitors in two phase III clinical trials, indicating its safety and efficacy in delaying disease progression and supporting its use as a front-line therapy for PsA (249, 553, 554) .

Lxekizumab was initially approved in 2016 by the US FDA for moderate to severe plaque psoriasis treatment in adult patients who are eligible for systematic therapy or phototherapy. The FDA approval was further expanded in 2017 for the treatment of adults suffering from active PsA. Furthermore, the US FDA approved Ixekizumab in 2019 for the treatment of active ankylosing spondylitis in adults. In early 2020, Ixekizumab has also granted the US FDA approval for the treatment of pediatric patients (ages 6 to 18) with moderate to severe plaque psoriasis who are also eligible for systemic therapy or phototherapy. Currently, ixekizumab is being evaluated in four active clinical trials. These include a phase IV clinical trial assessing the efficacy of ixekizumab in Japanese patients with generalized pustular psoriasis and erythrodermic psoriasis (NCT03942042). In addition, this mAb is also being tested in Chinese patients who have moderate to severe plaque psoriasis (NCT03364309).

Ranibizumab is a Fab antibody fragment derived from a recombinant humanized IgG1-κ mAb (murine Mab A.4.6.1) (555) . Ranibizumab was created from the same parent mouse antibody as bevacizumab to target VEGF-A, both bind effectively and neutralize VEGF-A isoforms (555) . VEGF-A and its receptors VEGFR-1 and VEGFR-2 promote angiogenesis throughout the body and represent the primary mediators of degenerative ocular conditions, such as diabetic retinopathy, retinal vein occlusions, age-related macular degeneration (AMD) including wet-AMD, the leading cause of blindness in the elderly population (556, 557) . Ranibizumab has smaller size than bevacizumab and readily penetrates all layers of the retina after intravitreal injection (558) . Importantly, ranibizumab is thought to be safer on normal healthy cells that express VEGF-A as it has shorter serum half-life and faster system clearance (559) . Currently, there are 18 active clinical trials to evaluate ranibizumab as single or in combination with other treatments. One phase IV clinical study is comparing the safety and efficacy between ranibizumab as monotherapy and in combination with R:GEN (selective retina therapy) in clinically significant diabetic macular edema (NCT03759860). Also, another phase IV clinical study is comparing intravitreal ranibizumab and triamcinolone acetonide combination therapy vs. ranibizumab monotherapy in patients with polypoidal choroidal vasculopathy (NCT02806752). Long-term efficacy and safety of intravitreal ranibizumab compared with laser ablation therapy in patients who were treated for retinopathy of prematurity (ROP) (NCT02640664) is in phase III stage.

Caplacizumab is a humanized bivalent single-variable domain immunoglobulin (VHH) that consists of two identical, genetically linked, humanized building blocks (298) . Caplacizumab was generated for the treatment of platelet adhesion diseases, such as acquired thrombotic thrombocytopenic purpura (aTTP) (298) . Caplacizumab binds specifically to human von Willebrand factor (vWF) A1 domain, preventing its binding to the platelet glycoprotein 1b receptor (298) . Acquired TTP is a rare blood disorder characterized by thrombosis in small blood vessels and low platelet count. It is caused by a severe deficiency in the vWF-cleaving protease (ADAMTS13) primarily due to acquired autoantibodies (560) . Lacking ADAMTS13 enhances the accumulation of large multimers of vWF, vWF-platelet aggregation, and microvascular thrombosis of TTP, leading to low platelet count, ischemia, and organ dysfunction (560, 561) .

Clinical studies showed that treatment with caplacizumab transiently reduced vWF levels and normalized platelet count compared with placebo (562) . Target-bound caplacizumab is thought to be metabolized within the liver, while unbound caplacizumab is cleared renally (299) . Caplacizumab received its first approval in September 2018 in the EU for the treatment of adults experiencing aTTP in conjunction with plasma exchange and immunosuppression (corticosteroids and increasingly also rituximab) (11) . Caplacizumab is the first nanobody-based medication to receive approval in the US in 2019, for patients aged ≥18 years experiencing aTTP (11) . Currently, one active phase III clinical trial (NCT02878603) is evaluating the longterm safety and efficacy of repeated use of caplacizumab in aTTP patients.

Emapalumab is a human IgG1-λ mAb that neutralizes interferon gamma (IFNγ) activities and inhibits its binding to the interferon receptors (IFNγR1 and IFNγR2). It binds with high affinity to free and receptor-bound IFNγ, preventing the downstream signaling of JAK/STAT pathway and the subsequent cytokine storm release (563, 564) . This blockade results in the attenuation of the adaptive and innate immune responses, which increase the susceptibility to infections (564) . It has been primarily developed to treat patients with haemophagocytic lymphohistiocytosis (HLH) disorder refractory to conventional therapy (565, 566) . HLH is a rare pathologic immune activation syndrome with excessive inflammation that occurs as a familial or sporadic disorder due to a variety of immune triggers (567) .

A phase I dose-escalation clinical trial investigating the safety in healthy subjects, revealed a favorable safety profile warranting further clinical development (NCT01459562). Emapalumab was then evaluated in an open-label phase II/III trial in 34 pediatric patients with a confirmed HLH disorder. Emapalumab was administered with dexamethasone intravenously every 3-4 days for a minimum of 4 weeks and up to 8 weeks with a primary endpoint of overall response rate (ORR) (NCT01818492). Patients have experienced a response rates above 70 with a safe and tolerable profile and mild-moderate infusion-related reactions in 27% of the patients confirming its favorable outcomes (568) . This trial has led to the US FDA approval of emapalumab in 2018 as an IFN blocking molecule for pediatric and adult patients with HLH refractory to conventional therapy (dexamethasone, etoposide, and intrathecal methotrexate) (565, 566) . Currently, the efficacy of emapalumab is being evaluated in four active phase II/III clinical trials in patients with primary and secondary HLH (NCT03312751, NCT03985423, NCT01818492, NCT03311854). In addition, the safety and efficacy of emapalumab are also being tested in COVID-19 patients, with a primary endpoint of reducing the number of patients who need invasive mechanical ventilation or extracorporeal membrane oxygenation (NCT04324021).

Antibody phage display is a versatile, reproducible, and functional technology that can be utilized to isolate antibody candidates for numerous disease indications. While it is the most common and well-established form of display technologies, the success of isolating useful antibodies is highly dependent on the quality and the nature of the targeted antigen used in biopanning and the size and quality of the library. By performing cell-based biopanning, antibody phage display can be used to identify new cell biomarkers, isolate antibodies that can discriminate between different antigen epitopes and conformations, or identify antibodies against antigens that are not available in pure form (74) .

Phage display technology has been proven to be a powerful human mAb discovery platform. Not long ago the commercial use of phage display was restricted to a few selected biopharmaceutical companies with rights to phage display intellectual property (569) . This explains why most of the approved mAbs or those in clinical trials sourced from phage display libraries belong to commercial entities with rights to the technology. However, most of the key patents covering phage display technology have expired in Europe and the US (569) . Consequently, patent expiration should encourage academic and biotech start-ups to develop their own libraries to generate and develop more antibodies for translation to the clinic.

By reflecting on the collected data, antibody phage display has contributed to the isolation of antibodies for the treatment of many disease indications. There are 14 FDA approved phage display-derived antibodies and antibody fragments, and many others in clinical trials. Many research institutes, start-ups and industrial laboratories are continually developing methods for the design, construction and screening of developable antibodyphage libraries. Further improvements are expected to be achieved in the near future as this technology contributes significantly toward research, diagnosis, and therapy.

MA and AH designed the review. MA, HA, AM, AA, and MJ wrote the main manuscript text. MA prepared the figures and analyzed the data. MJ, SM, and AH provided a substantial contribution to the discussion of the content and helped with reviewing and editing the article. All authors read and approved the final manuscript. 

Building better monoclonal antibody-based therapeutics

Engineering antibody heavy chain CDR3 to create a phage display Fab library rich in antibodies that bind charged carbohydrates

Anti-PEG antibodies in the clinic: Current issues and beyond PEGylation

Human anti-gold antibodies: biofunctionalization of gold nanoparticles and surfaces with anti-gold antibodies

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The increasingly human and profitable monoclonal antibody market

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Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface

Phage antibodies: filamentous phage displaying antibody variable domains

Man-made antibodies

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Human anti-mouse antibody response to the injection of murine monoclonal antibodies against IL-6

Therapeutic applications of monoclonal antibodies

Genetically engineered antibody molecules

Human-engineered monoclonal antibodies retain full specific binding activity by preserving non-CDR complementarity-modulating residues

Replacing the complementarity-determining regions in a human antibody with those from a mouse

Antigen-specific human antibodies from mice comprising four distinct genetic modifications

Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice

The physical and functional behavior of capture antibodies adsorbed on polystyrene

Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a herceptin-resistant, MUC4-expressing breast cancer cell line

An entirely cell-based system to generate single-chain antibodies against cell surface receptors

Targeting membrane proteins for antibody discovery using phage display

Strategies for selecting membrane protein-specific antibodies using phage display with cell-based panning

Canine CD117-specific antibodies with diverse binding properties isolated from a phage display library using cell-based biopanning

Biopanning of phage displayed peptide libraries for the isolation of cell-specific ligands

Selection of anti-cancer antibodies from combinatorial libraries by whole-cell panning and stringent subtraction with human blood cells

Selection of tumor-binding ligands in cancer patients with phage display libraries

Antibody phage display libraries: contributions to oncology

Phage display of combinatorial antibody libraries

Subtractive single-chain antibody (scFv) phage-display: tailoring phage-display for high specificity against function-specific conformations of cell membrane molecules

Single-chain antibodies for the conformation-specific blockade of activated platelet integrin alphaIIbbeta3 designed by subtractive selection from naive human phage libraries

Conformation-specific blockade of the integrin GPIIb/IIIa: a novel antiplatelet strategy that selectively targets activated platelets

Generation of activation-specific human anti-alphaMbeta2 single-chain antibodies as potential diagnostic tools and therapeutic agents

Generating conformation-specific synthetic antibodies to trap proteins in selected functional states

Microselection-affinity selecting antibodies against a single rare cell in a heterogeneous population

Selection of antibodies against a single rare cell present in a heterogeneous population using phage display

Machine learning-guided prediction of antigen-reactive in silico clonotypes based on changes in clonal abundance through bio-panning

High-throughput sequencing of the paired human immunoglobulin heavy and light chain repertoire

Third generation antibody discovery methods: in silico rational design

High-throughput retrieval of physical DNA for NGS-identifiable clones in phage display library

Retooling phage display with electrohydrodynamic nanomixing and nanopore sequencing

Developing therapeutic monoclonal antibodies at pandemic pace

Isolation of high affinity human antibodies directly from large synthetic repertoires

Prediction of aggregation prone regions of therapeutic proteins

Biophysical properties of the clinical-stage antibody landscape

Sequence features of variable region determining physicochemical properties and polyreactivity of therapeutic antibodies

Early developability screen of therapeutic antibody candidates using Taylor dispersion analysis and UV area imaging detection. mAbs

Engineering the surface properties of a human monoclonal antibody prevents self-association and rapid clearance in vivo

Biopharmaceutical liquid formulation: a review of the science of protein stability and solubility in aqueous environments

High-concentration protein formulations: how high is high

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Boosting antibody developability through rational sequence optimization. mAbs

Design of therapeutic proteins with enhanced stability

Aggregation, stability, and formulation of human antibody therapeutics

Engineering aggregation-resistant antibodies

Effects of protein aggregates: an immunologic perspective

Antibodies from phage antibody libraries

Rapid isolation of intrabody candidates by using an optimized non-immune phage antibody library

Generation, diversity determination, and application to antibody selection of a human naive Fab library

Generation and analysis of the improved human HAL9/10 antibody phage display libraries

Discovery of diverse and functional antibodies from large human repertoire antibody libraries

Phage display libraries for antibody therapeutic discovery and development

The diversity of H3 loops determines the antigenbinding tendencies of antibody CDR loops

The structural basis of antibody-antigen recognition

Identification of specificitydetermining residues in antibodies

The indistinguishability of epitopes from protein surface is explained by the distinct binding preferences of each of the six antigen-binding loops

Standard conformations for the canonical structures of immunoglobulins

A systematic comparison of free and bound antibodies reveals binding-related conformational changes

Conformations of immunoglobulin hypervariable regions

Canonical structures for the hypervariable regions of immunoglobulins

H3-rules: identification of CDR-H3 structures in antibodies

Phage display antibody libraries: a robust approach for generation of recombinant human monoclonal antibodies

Diversity in the CDR3 region of V(H) is sufficient for most antibody specificities

Efficient construction and effective screening of synthetic domain antibody libraries

Design and use of a phage display library. Human antibodies with subnanomolar affinity against a marker of angiogenesis eluted from a two-dimensional gel

Semisynthetic combinatorial antibody libraries: a chemical solution to the diversity problem

Human combinatorial Fab library yielding specific and functional antibodies against the human fibroblast growth factor receptor 3

Drugs derived from phage display: from candidate identification to clinical practice

Phage display-derived human antibodies in clinical development and therapy

Human antibodies with sub-nanomolar affinities isolated from a large non-immunized phage display library

Modelling the human immune response: performance of a 1011 human antibody repertoire against a broad panel of therapeutically relevant antigens

Affinity maturation of phage display antibody populations using ribosome display

A large non-immunized human Fab fragment phage library that permits rapid isolation and kinetic analysis of high affinity antibodies

Fully synthetic human combinatorial antibody libraries (HuCAL) based on modular consensus frameworks and CDRs randomized with trinucleotides

The human combinatorial antibody library HuCAL GOLD combines diversification of all six CDRs according to the natural immune system with a novel display method for efficient selection of high-affinity antibodies

HuCAL PLATINUM, a synthetic Fab library optimized for sequence diversity and superior performance in mammalian expression systems

Guiding the selection of human antibodies from phage display repertoires to a single epitope of an antigen

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Isolation of a high-affinity stable single-chain Fv specific for mesothelin from DNA-immunized mice by phage display and construction of a recombinant immunotoxin with anti-tumor activity

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Therapeutic antibodies by phage display

Avelumab (anti-PD-L1) in platinum-resistant/refractory ovarian cancer: JAVELIN Ovarian 200 Phase III study design

Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300

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Avelumab: a review in metastatic merkel cell carcinoma

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Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator

The discovery and development of belimumab: the anti-BLyS-lupus connection

Belimumab alters transitional B-cell subset proportions in patients with stable systemic lupus erythematosus

Efficacy and safety of belimumab and azathioprine for maintenance of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled study

A potent human anti-eotaxin1 antibody, CAT-213: isolation by phage display and in vitro and in vivo efficacy

Biologics in chronic rhinosinusitis: an update and thoughts for future directions

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Healthcare utilisation prior to the diagnosis of inflammatory bowel diseases and the influence of livestock exposure: a longitudinal case-control study

An antibody blocking activin type II receptors induces strong skeletal muscle hypertrophy and protects from atrophy

Bimagrumab improves body composition and insulin sensitivity in insulin-resistant individuals

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an anti-C-C chemokine ligand 2 monoclonal antibody, in combination with four chemotherapy regimens for the treatment of patients with solid tumors: an open-label, multicenter phase 1b study

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Focal irradiation and systemic TGFbeta blockade in metastatic breast cancer

Generation and characterization of ixekizumab, a humanized monoclonal antibody that neutralizes interleukin-17A

Safety of ixekizumab in patients with psoriatic arthritis: results from a pooled analysis of three clinical trials

A phase II randomized study of subcutaneous ixekizumab, an anti-interleukin-17 monoclonal antibody, in rheumatoid arthritis patients who were naive to biologic agents or had an inadequate response to tumor necrosis factor inhibitors

Efficacy and safety of ixekizumab in the treatment of radiographic axial spondyloarthritis: sixteen-week results from a phase III randomized, double-blind, placebo-controlled trial in patients with prior inadequate response to or intolerance of tumor necrosis factor inhibitors

Long-term efficacy and safety of ixekizumab in Japanese patients with erythrodermic or generalized pustular psoriasis: subgroup analyses of an open-label, phase 3 study (UNCOVER-J)

HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo

A multicenter randomized phase II trial of mapatumumab, a TRAIL-R1 agonist monoclonal antibody, in combination with bortezomib in patients with relapsed/refractory multiple myeloma (MM)

A phase 1b/2 trial of mapatumumab in patients with relapsed/refractory non-Hodgkin's lymphoma

Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptoralpha, in subjects with rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase I, first-in-human study

A randomized phase IIb study of mavrilimumab and golimumab in rheumatoid arthritis

Targeting granulocyte-monocyte colony-stimulating factor signaling in rheumatoid arthritis: future prospects

Antibody fusion proteins: anti-CD22 recombinant immunotoxin moxetumomab pasudotox

Moxetumomab pasudotox-tdfk for relapsed/refractory hairy cell leukemia: a review of clinical considerations

Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia

A highly stable polyethylene glycol-conjugated human single-chain antibody neutralizing granulocyte-macrophage colony stimulating factor at low nanomolar concentration

A human monoclonal IgG1 potently neutralizing the pro-inflammatory cytokine GM-CSF

Efficacy and safety of namilumab, a human monoclonal antibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) ligand in patients with rheumatoid arthritis (RA) with either an inadequate response to background methotrexate therapy or an inadequate response or intolerance to an anti-TNF (tumour necrosis factor) biologic therapy: a randomized, controlled trial

Novel therapeutic targets in axial spondyloarthritis

Granulocyte-macrophage colony-stimulating factor (GM-CSF) as a therapeutic target in psoriasis: randomized, controlled investigation using namilumab, a specific human anti-GM-CSF monoclonal antibody

Structural basis for EGF receptor inhibition by the therapeutic antibody IMC-11F8

Identification and characterization of a fully human antibody directed against epidermal growth factor receptor for cancer therapy

A randomized, multicenter, open-label, phase III study of gemcitabinecisplatin (GC) chemotherapy plus necitumumab (IMC-11F8/LY3012211) versus GC alone in the first-line treatment of patients (pts) with stage IV squamous non-small cell lung cancer (sq-NSCLC)

Necitumumab for the treatment of advanced non-small-cell lung cancer

Phase II study of necitumumab plus modified FOLFOX6 as first-line treatment in patients with locally advanced or metastatic colorectal cancer

A phase I pharmacologic study of necitumumab (IMC-11F8), a fully human IgG1 monoclonal antibody directed against EGFR in patients with advanced solid malignancies

Exposure levels of anti-LINGO-1 Li81 antibody in the central nervous system and dose-efficacy relationships in rat spinal cord remyelination models after systemic administration

Safety and efficacy of opicinumab in patients with relapsing multiple sclerosis (SYNERGY): a randomised, placebo-controlled, phase 2 trial

Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial

TTAC-0001, a human monoclonal antibody targeting VEGFR-2/KDR, blocks tumor angiogenesis

Construction of scFv fragments from hybridoma or spleen cells by PCR assembly

Phase I trial and pharmacokinetic study of tanibirumab, a fully human monoclonal antibody to vascular endothelial growth factor receptor 2, in patients with refractory solid tumors

A multicenter, 3-arm, open-label, phase IIa clinical trial to evaluate the safety and efficacy of tanibirumab (VEGFR2 mAb), in patients with recurrent glioblastoma (GBM)

Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity

Phase Ib study of utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in combination with pembrolizumab (MK-3475) in patients with advanced solid tumors

Innovative Strategies: Targeting Subtypes in Metastatic Breast Cancer

Cancer immunotherapy in diffuse large B-cell lymphoma

CAR T-cell therapy for B-cell lymphomas: clinical trial results of available products

Non-Hodgkin lymphoma therapy landscape

AMG 479, a fully human anti-insulin-like growth factor receptor type I monoclonal antibody, inhibits the growth and survival of pancreatic carcinoma cells

Epitopespecific mechanisms of IGF1R inhibition by ganitumab

A randomized, placebo-controlled phase 2 study of ganitumab or conatumumab in combination with FOLFIRI for second-line treatment of mutant KRAS metastatic colorectal cancer

A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial

Emerging novel agents for patients with advanced Ewing sarcoma: a report from the Children's Oncology Group (COG) New Agents for Ewing Sarcoma Task Force

Abstract 1022: development and preclinical testing of AMG 780, a fully human antibody targeting angiopoietin 1 (Ang1) and angiopoietin 2 (Ang2)

A phase I, first-in-human study of AMG 780, an angiopoietin-1 and−2 inhibitor, in patients with advanced solid tumors

Naturally occurring antibodies devoid of light chains

Properties, production, and applications of camelid single-domain antibody fragments

Antithrombotic drug candidate ALX-0081 shows superior preclinical efficacy and safety compared with currently marketed antiplatelet drugs

Caplacizumab: first global approval

Results of the randomized, double-blind, placebocontrolled, phase 3 Hercules study of caplacizumab in patients with acquired thrombotic thrombocytopenic purpura

Selection of high affinity human neutralizing antibodies to VEGFR2 from a large antibody phage display library for antiangiogenesis therapy

Tailoring in vitro selection for a picomolar affinity human antibody directed against vascular endothelial growth factor receptor 2 for enhanced neutralizing activity

Phase I study of every 2-or 3-week dosing of ramucirumab, a human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2 in patients with advanced solid tumors

RELEVENT trial: phase II trial of ramucirumab, carboplatin, and paclitaxel in previously untreated thymic carcinoma/B3 thymoma with area of carcinoma

Primary results of ROSE/TRIO-12, a randomized placebo-controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer

Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial

Ramucirumab for the treatment of gastric or gastroesophageal junction cancer

Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial

Ramucirumab in metastatic colorectal cancer: evidence to date and place in therapy

Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial

Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders

VEGF and the Fab fragment of a humanized neutralizing antibody: crystal structure of the complex at 2.4 Å resolution and mutational analysis of the interface

Selection and analysis of an optimized anti-VEGF antibody: crystal structure of an affinity-matured fab in complex with antigen

Ranibizumab induces regression of diabetic retinopathy in most patients at high risk of progression to proliferative diabetic retinopathy

Action on neovascular age-related macular degeneration (nAMD): recommendations for management and service provision in the UK hospital eye service

Ranibizumab for macular edema following central retinal vein occlusion: sixmonth primary end point results of a phase III study

Ranibizumab in the treatment of diabetic macular edema: a review of the current status, unmet needs, and emerging challenges

Real-world data on ranibizumab for myopic choroidal neovascularization due to pathologic myopia: results from a post-marketing surveillance in Japan

A review of ranibizumab for the treatment of diabetic retinopathy

Fully human antibody MOR202 against CD38 for the treatment of multiple myeloma and other blood-borne malignancies

Phase I/IIa study of the human anti-CD38 antibody MOR202

MOR03087) in relapsed or refractory multiple myeloma

Enhancement of the antitumor properties of interleukin-2 by its targeted delivery to the tumor blood vessel extracellular matrix

The tumour-targeting human L19-IL2 immunocytokine: preclinical safety studies, phase I clinical trial in patients with solid tumours and expansion into patients with advanced renal cell carcinoma

The challenges and molecular approaches surrounding interleukin-2-based therapeutics in cancer

Selective targeted delivery of TNFalpha to tumor blood vessels

The antibody-based targeted delivery of TNF in combination with doxorubicin eradicates sarcomas in mice and confers protective immunity

Antibody-cytokine fusion proteins: a novel class of biopharmaceuticals for the therapy of cancer and of chronic inflammation

Selective targeting of tumoral vasculature: comparison of different formats of an antibody (L19) to the ED-B domain of fibronectin

Radretumab radioimmunotherapy in patients with brain metastasis: a 124 I-L19SIP dosimetric PET study

Radioimmunotherapy with radretumab in patients with relapsed hematologic malignancies

Approval of raxibacumab for the treatment of inhalation anthrax under the US Food and Drug Administration

vitro affinity maturation of human GM-CSF antibodies by targeted CDR-diversification

OP0228 GSK3196165 an investigational anti-GM-CSF monoclonal antibody, improves patient reported outcomes in a phase IIb study of patients with rheumatoid arthritis (RA)

Investigational therapies targeting the granulocyte macrophage colony-stimulating factor receptor-α in rheumatoid arthritis: focus on mavrilimumab

Therapeutically targeting ErbB3: a key node in ligandinduced activation of the ErbB receptor-PI3K axis

Highthroughput affinity ranking of antibodies using surface plasmon resonance microarrays

Seribantumab, an anti-ERBB3 antibody, delays the onset of resistance and restores sensitivity to letrozole in an estrogen receptor-positive breast cancer model

Randomized phase II trial of seribantumab in combination with erlotinib in patients with EGFR wild-type non-small cell lung cancer

Probing a protein-protein interaction by in vitro evolution

Preclinical development of CAT-354, an IL-13 neutralizing antibody, for the treatment of severe uncontrolled asthma

Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): two randomised, double-blind, placebo-controlled, phase 3 clinical trials

Effector-mediated eradication of precursor B acute lymphoblastic leukemia with a novel Fc-engineered monoclonal antibody targeting the BAFF-R

Establishment of FUT8 knockout Chinese hamster ovary cells: an ideal host cell line for producing completely defucosylated antibodies with enhanced antibody-dependent cellular cytotoxicity

Anti-BAFF-R antibody VAY-736 demonstrates promising preclinical activity in CLL and enhances effectiveness of ibrutinib

Treatment of primary Sjögren's syndrome with ianalumab (VAY736) targeting B cells by BAFF receptor blockade coupled with enhanced, antibody-dependent cellular cytotoxicity

B-cell-targeted therapies in relapsing forms of MS

Tumor-targeting properties of novel antibodies specific to the large isoform of tenascin-C

Antibody-mediated delivery of interleukin-2 to the stroma of breast cancer strongly enhances the potency of chemotherapy

Design and use of phage display libraries for the selection of antibodies and enzymes

Targeting interleukin-2 to the bone marrow stroma for therapy of acute myeloid leukemia relapsing after allogeneic hematopoietic stem cell transplantation

Systemic therapy for merkel cell carcinoma: what's on the horizon? Cancers (Basel)

Immunocytokines: a review of molecules in clinical development for cancer therapy

Pharmacodynamic and antineoplastic activity of BI 836845, a fully human IGF ligand-neutralizing antibody, and mechanistic rationale for combination with rapamycin

02b-005 phase Ib trial of afatinib and BI 836845 in advanced NSCLC: dose escalation and safety results: topic: EGFR biomarkers

Phase I dose escalation study of 3-weekly BI 836845, a fully human, affinity optimized, insulin-like growth factor (IGF) ligand neutralizing antibody, in patients with advanced solid tumors

Insulin-like growth factor (IGF) pathway targeting in cancer: role of the IGF axis and opportunities for future combination studies

XENERA-1: A phase II trial of xentuzumab (Xe) in combination with everolimus (Ev) and exemestane (Ex) in patients with hormone receptorpositive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) and non-visceral involvement

Compositions and Methods for Use for Antibodies Against Sclerostin. US patent US 7879322 B2

BPS804 anti-sclerostin antibody in adults with moderate osteogenesis imperfecta: results of a randomized phase 2a trial

Efficacy of anti-sclerostin monoclonal antibody BPS804 in adult patients with hypophosphatasia

Sclerostin antibody therapy for the treatment of osteoporosis: clinical prospects and challenges

Involvement of the VEGF receptor 3 in tubular morphogenesis demonstrated with a human anti-human VEGFR-3 monoclonal antibody that antagonizes receptor activation by VEGF-C

Phase 1 study of the anti-vascular endothelial growth factor receptor 3 monoclonal antibody LY3022856/IMC-3C5 in patients with advanced and refractory solid tumors and advanced colorectal cancer

Preclinical efficacy of the auristatin-based antibody-drug conjugate BAY 1187982 for the treatment of FGFR2-positive solid tumors

Recombining germline-derived CDR sequences for creating diverse single-framework antibody libraries

Abstract 4766: pharmacodynamic and stratification biomarker for the anti-FGFR2 antibody (BAY1179470) and the FGFR2-ADC

Bayer Health Care LLC. Monoclonal Antibodies Against Tissue Factor Pathway Inhibitor (TFPI). US patent US

Characterization of a high-affinity fully human IgG2 antibody against tissue factor pathway inhibitor as a bypass agent for the treatment of hemophilia

Antibody engineering of anti-TFPI bypass therapeutic BAY 1093884: isotype selection and sequence optimization

BAY 1213790, a fully human IgG1 antibody targeting coagulation factor XIa: first evaluation of safety, pharmacodynamics, and pharmacokinetics

Allosteric inhibition as a new mode of action for BAY 1213790, a neutralizing antibody targeting the activated form of coagulation factor XI

Factor XIa inhibitors as new anticoagulants

Il-17a Antibodies. US patent US 8519107 B2

CNTO6785, a fully human antiinterleukin 17 monoclonal antibody, in patients with rheumatoid arthritis with inadequate response to methotrexate: a randomized, placebo-controlled, phase II, dose-ranging study

A randomized, placebo-controlled phase 2 trial of CNTO 6785 in chronic obstructive pulmonary disease

Toll-like Receptor 3 Antagonists. US patent US 8409567 B2

Toll-like receptor 3 blockade in rhinovirus-induced experimental asthma exacerbations: a randomized controlled study

Safety and efficacy of ABT-874, a fully human interleukin 12/23 monoclonal antibody, in the treatment of moderate to severe chronic plaque psoriasis: results of a randomized, placebo-controlled, phase 2 trial

ABT-874, a fully human monoclonal anti-IL-12/IL-23 antibody for the potential treatment of autoimmune diseases

A phase 2, 24-week, randomized, placebo-controlled, double-blind study examining the efficacy and safety of an anti-interleukin-12 and−23 monoclonal antibody in patients with relapsing-remitting or secondary progressive multiple sclerosis

Efficacy and safety results from a phase III, randomized controlled trial comparing the safety and efficacy of briakinumab with etanercept and placebo in patients with moderate to severe chronic plaque psoriasis

BHQ880, a novel anti-DKK1 neutralizing antibody, inhibits tumor-induced osteolytic bone disease

A phase I/II study of BHQ880, a novel osteoblat activating, anti-DKK1 human monoclonal antibody, in relapsed and refractory multiple myeloma (MM) patients treated with zoledronic acid (Zol) and anti-myeloma therapy (MM Tx)

Early evidence of anabolic bone activity of BHQ880, a fully human anti-DKK1 neutralizing antibody: results of a phase 2 study in previously untreated patients with smoldering multiple myeloma at risk for progression

Antagonistic human FcgammaRIIB (CD32B) antibodies have anti-tumor activity and overcome resistance to antibody therapy in vivo

Targeting the antibody checkpoints to enhance cancer immunotherapy-focus on FcgammaRIIB

A high-affinity human monoclonal antibody specific to the alternatively spliced EDA domain of fibronectin efficiently targets tumor neo-vasculature in vivo

FRI0118 Dekavil (F8IL10)-update on the results of clinical trials investigating the immunocytokine in patients with rheumatoid arthritis

In vitro and in vivo characterization of a human anti-c-erbB-2 single-chain Fv isolated from a filamentous phage antibody library

Selection and characterization of cell binding and internalizing phage antibodies

HERMIONE: a randomized phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician's choice plus trastuzumab in patients with previously treated, anthracycline-naïve, HER2-positive, locally advanced/metastatic breast cancer

Safety and pharmacokinetics of MM-302, a HER2-targeted antibody-liposomal doxorubicin conjugate, in patients with advanced HER2-positive breast cancer: a phase 1 dose-escalation study

Human Anti-il-23 Antibodies, Compositions, Methods and Uses. US patent US 9353181 B2

Antibody modeling assessment II. Structures and models

Guselkumab: first global approval

A randomised phase II study evaluating the efficacy and safety of subcutaneously administered ustekinumab and guselkumab in patients with active rheumatoid arthritis despite treatment with methotrexate

Efficacy and safety of guselkumab, an anti-interleukin 23 monoclonal antibody, for palmoplantar pustulosis: a randomized clinical trial

Preclinical antitumor efficacy of BAY 1129980-a novel auristatin-based anti-C4.4A (LYPD3) antibody-drug conjugate for the treatment of non-small cell lung cancer

Inhibition of plasma kallikrein by a highly specific active site blocking antibody

Effect of lanadelumab compared with placebo on prevention of hereditary angioedema attacks: a randomized clinical trial

Lanadelumab: first global approval

Phase I trial and pharmacokinetic study of lexatumumab in pediatric patients with solid tumors

A phase Ib study to assess the safety of lexatumumab, a human monoclonal antibody that activates TRAIL-R2, in combination with gemcitabine, pemetrexed, doxorubicin or FOLFIRI

Targeting CD73 in the tumor microenvironment with MEDI9447

Safety, efficacy and pharmacodynamics (PD) of MEDI9447 (oleclumab) alone or in combination with durvalumab in advanced colorectal cancer (CRC) or pancreatic cancer (panc)

04-23 phase 1b/2 study to evaluate novel combinations with oleclumab (MEDI9447) in previously treated advanced EGFRm NSCLC

Abstract OT3-01-01: BEGONIA: phase Ib/II open-label, platform study of safety and efficacy of durvalumab, paclitaxel and other novel oncology therapy agents as first-line (1L) therapy in patients with metastatic triple negative breast cancer (mTNBC)

Targeting notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency

A phase 1 dose escalation and expansion study of tarextumab (OMP-59R5) in patients with solid tumors

Results of a randomized phase II trial of an anti-notch 2/3, tarextumab (OMP-59R5, TRXT, anti-Notch2/3), in combination with nab-paclitaxel and gemcitabine (Nab-P+Gem) in patients (pts) with untreated metastatic pancreatic cancer (mPC)

A randomized phase II trial of nab-paclitaxel and gemcitabine with tarextumab or placebo in patients with untreated metastatic pancreatic cancer

New opportunities and challenges to defeat cancer stem cells. Trends Cancer

An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin

In vitro affinity maturation of HuCAL antibodies: complementarity determining region exchange and RapMAT technology

A phase I open-label dose-escalation study of the anti-HER3 monoclonal antibody LJM716 in patients with advanced squamous cell carcinoma of the esophagus or head and neck and HER2-overexpressing breast or gastric cancer

LJM716 in Japanese patients with head and neck squamous cell carcinoma or HER2-overexpressing breast or gastric cancer

Targeting HER3 using monoand bispecific antibodies or alternative scaffolds

HER3 signaling and targeted therapy in cancer

Gantenerumab: a novel human anti-abeta antibody demonstrates sustained cerebral amyloid-beta binding and elicits cellmediated removal of human amyloid-beta

A phase III randomized trial of gantenerumab in prodromal Alzheimer's disease

Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors

First-in-human evaluation of the human monoclonal antibody vantictumab (OMP-18R5; anti-Frizzled) targeting the WNT pathway in a phase I study for patients with advanced solid tumors

WNT antagonists exhibit unique combinatorial antitumor activity with taxanes by potentiating mitotic cell death

A novel IgE-neutralizing antibody for the treatment of severe uncontrolled asthma

Pharmacokinetics, pharmacodynamics, and safety of MEDI4212, an anti-IgE monoclonal antibody, in subjects with atopy: a phase I study

Structural and functional analysis of the interaction between the agonistic monoclonal antibody Apomab and the proapoptotic receptor DR5

A phase I safety and pharmacokinetic study of the death receptor 5 agonistic antibody PRO95780 in patients with advanced malignancies

Phase II study of PRO95780 plus rituximab in patients with relapsed follicular non-Hodgkin's lymphoma (NHL)

Phase II study of PRO95780 plus paclitaxel, carboplatin, and bevacizumab (PCB) in non-small cell lung cancer (NSCLC)

Generation and characterization of LFG316, a fully-human anti-C5 antibody for the treatment of age-related macular degeneration

Therapeutic approaches with intravitreal injections in geographic atrophy secondary to age-related macular degeneration: current drugs and potential molecules

The renaissance of complement therapeutics

Anti-interferon Gamma Antibodies and Methods of Use Thereof. US patent US 9682142 B2

Emapalumab: first global approval

Anti Mif Antibodies. EP patent EP 2231707 B1

PD-011Safety and efficacy analysis of imalumab, an anti-oxidized macrophage migration inhibitory factor (oxMIF) antibody, alone or in combination with 5-fluorouracil/leucovorin (5-FU/LV) or panitumumab, in patients with metastatic colorectal cancer (mCRC)

The management of malignant ascites and impact on quality of life outcomes in women with ovarian cancer. Expert Rev Qual Life Cancer Care

FDG-PET imaging for oxidized LDL in stable atherosclerotic disease: a phase II study of safety, tolerability, and anti-inflammatory activity

A single-arm, open-label, phase 2 clinical trial evaluating disease response following treatment with BI-505, a human anti-intercellular adhesion molecule-1 monoclonal antibody, in patients with smoldering multiple myeloma

Recombinant mAb libraries: screening for new therapeutics

New Antibodies Against Phosphorylcholine. EP patent EP 2742068 B1

Abstract 15644: a fully human monoclonal IgG phosphorylcholine antibody prevents accelerated atherosclerosis in mice

Vaccination strategies and immune modulation of atherosclerosis

Potent neutralization of Hendra and Nipah viruses by human monoclonal antibodies

Exceptionally potent cross-reactive neutralization of Nipah and Hendra viruses by a human monoclonal antibody

Safety, tolerability, pharmacokinetics, and immunogenicity of a human monoclonal antibody targeting the G glycoprotein of henipaviruses in healthy adults: a first-in-human, randomised, controlled, phase 1 study

ARGX-110, a highly potent antibody targeting CD70, eliminates tumors via both enhanced ADCC and immune checkpoint blockade

Camelid Ig V genes reveal significant human homology not seen in therapeutic target genes, providing for a powerful therapeutic antibody platform. mAbs

The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity

Argx-110 targeting CD70, in combination with azacitidine, shows favorable safety profile and promising anti-leukemia activity in newly diagnosed AML patients in an ongoing phase 1/2 clinical trial

Phase I dose-escalation study of the anti-CD70 antibody ARGX-110 in advanced malignancies

Four individually druggable MET hotspots mediate HGF-driven tumor progression

Depleting MET-expressing tumor cells by ADCC provides a therapeutic advantage over inhibiting HGF/MET signaling

Divergent activities of an engineered antibody in murine and human systems have implications for therapeutic antibodies

A phase I, first-in-human study of argx-111, a monoclonal antibody targeting c-met in patients with solid tumors

Assessing the immunogenicity of biopharmaceuticals

Next generation antibody drugs: pursuit of the 'high-hanging fruit

Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up

Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer

Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial

Nivolumab versus everolimus in advanced renal-cell carcinoma

Pembrolizumab versus ipilimumab in advanced melanoma

Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial

Merkel cell carcinoma therapeutic update

PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome

Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial

Pembrolizumab versus investigator-choice chemotherapy for ipilimumabrefractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial

Avelumab for patients with previously treated metastatic or recurrent nonsmall-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial

Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial

Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced cancer: safety data from 1300 patients enrolled in the phase 1b JAVELIN Solid Tumor trial

16LBA Phase II, single-arm trial (BIRCH) of atezolizumab as first-line or subsequent therapy for locally advanced or metastatic PD-L1-selected non-small cell lung cancer (NSCLC)

Clinical activity, safety and predictive biomarkers of the engineered antibody MPDL3280A (anti-PDL1) in non-small cell lung cancer (NSCLC): update from a phase Ia study

Clinical activity and safety from a phase II study (FIR) of MPDL3280A (anti-PDL1) in PD-L1-selected patients with non-small cell lung cancer (NSCLC)

A phase Ia study of MPDL3280A (anti-PDL1): updated response and survival data in urothelial bladder cancer (UBC)

Clinical activity and safety of atezolizumab in patients with recurrent glioblastoma

Atezolizumab, an anti-programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: long-term safety, clinical activity, and immune correlates from a phase Ia study

A fully human IgG1 anti-PD-L1 MAb in an in vitro assay enhances antigen-specific T-cell responses

Antibody-dependent cellular cytotoxicity activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells

Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial

Tivozanib: first global approval

Immunotoxins: a review of their use in cancer treatment

CAT-8015: a second-generation pseudomonas exotoxin A-based immunotherapy targeting CD22-expressing hematologic malignancies

Improved cytotoxic activity toward cell lines and fresh leukemia cells of a mutant anti-CD22 immunotoxin obtained by antibody phage display

US lymphoid malignancy statistics by World Health Organization subtypes

Hairy cell leukemia: clinical presentation and follow-up of 211 patients

Long-term follow-up of 233 patients with hairy cell leukaemia, treated initially with pentostatin or cladribine, at a median of 16 years from diagnosis

Contextualizing the use of moxetumomab pasudotox in the treatment of relapsed or refractory hairy cell leukemia

Interaction of antibodies with ErbB receptor extracellular regions

A fully human recombinant IgG-like bispecific antibody to both the epidermal growth factor receptor and the insulin-like growth factor receptor for enhanced antitumor activity

The ErbB receptors and their ligands in cancer: an overview

Targeting the EGFR signaling pathway in cancer therapy

Epidermal growth factor receptor immunohistochemistry: comparison of antibodies and cutoff points to predict benefit from gefitinib in a phase 3 placebo-controlled study in advanced nonsmall-cell lung cancer

Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung

Portrazza (Necitumumab), an IgG1 monoclonal antibody, FDA approved for advanced squamous non-small-cell lung cancer

Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an openlabel, randomised, controlled phase 3 trial

Comparisons of affinities, avidities, and complement activation of adalimumab, infliximab, and etanercept in binding to soluble and membrane tumor necrosis factor

The tumor necrosis factor ligand and receptor families

Raxibacumab: potential role in the treatment of inhalational anthrax

Anthrax toxin: a tripartite lethal combination

Antibodies for biodefense

Anthrax as a biological weapon, 2002: updated recommendations for management

Anthrax lethal and edema toxins in anthrax pathogenesis

Raxibacumab for the treatment of inhalational anthrax

Belimumab: a review in systemic lupus erythematosus

The role of B lymphocyte stimulator (BLyS) in systemic lupus erythematosus

Normal B cell homeostasis requires B cell activation factor production by radiationresistant cells

Expression of BAFF (BLyS) in T cells infiltrating labial salivary glands from patients with Sjogren's syndrome

Synthesis and release of B-lymphocyte stimulator from myeloid cells

Aberrant expression of B-lymphocyte stimulator by B chronic lymphocytic leukemia cells: a mechanism for survival

G-CSF-stimulated neutrophils are a prominent source of functional BLyS

Selectivity of BAFF/BLyS and APRIL for binding to the TNF family receptors BAFFR/BR3 and BCMA

The BLyS/BAFF family of ligands and receptors: key targets in the therapy and understanding of autoimmunity

BLyS levels in sera of patients with systemic lupus erythematosus: clinical and serological correlation

Effect of long-term belimumab treatment on B cells in systemic lupus erythematosus: extension of a phase II, double-blind, placebo-controlled, dose-ranging study

B-celldepleting therapy in systemic lupus erythematosus

Ramucirumab: first global approval

Vascular endothelial growth factor receptors VEGFR-2 and VEGFR-3 are localized primarily to the vasculature in human primary solid cancers

Tumor cell expression of vascular endothelial growth factor receptor 2 is an adverse prognostic factor in patients with squamous cell carcinoma of the lung

FDA approval summary: ramucirumab for gastric cancer

Cyramza (Ramucirumab) approved for the treatment of advanced gastric cancer and metastatic non-small-cell lung cancer

Options for second-line treatment in metastatic colorectal cancer

Ramucirumab: a review in hepatocellular carcinoma

Guselkumab for the treatment of psoriasis-evidence to date

The secreted form of the p40 subunit of interleukin (IL)-12 inhibits IL-23 functions and abrogates IL-23-mediated antitumour effects

Interleukin-23: as a drug target for autoimmune inflammatory diseases

The role of IL 23 in the treatment of psoriasis

Human TH17 cells are long-lived effector memory cells

Efficacy and safety of guselkumab in patients with active psoriatic arthritis: a randomised, double-blind, placebo-controlled, phase 2 study

Guselkumab in patients with active psoriatic arthritis who were biologic-naive or had previously received TNFalpha inhibitor treatment (DISCOVER-1): a doubleblind, randomised, placebo-controlled phase 3 trial

IL-23 inhibitor guselkumab shows promise for PsA

Contact pathway of coagulation and inflammation

Contact system: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes

Highmolecular-weight kininogen cleavage correlates with disease states in the bradykinin-mediated angioedema due to hereditary C1-inhibitor deficiency

Role of bradykinin in mediating vascular effects of angiotensin-converting enzyme inhibitors in humans

Pathogenesis of hereditary angioedema: the role of the bradykinin-forming cascade

Mutation screening of C1 inhibitor gene in 108 unrelated families with hereditary angioedema: functional and structural correlates

Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor

A phase 1 study investigating DX-2930 in healthy subjects

Inhibiting plasma kallikrein for hereditary angioedema prophylaxis

Innate IL-17-producing cells: the sentinels of the immune system

Interleukin 17-producing CD4 + effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages

Tailored immune responses: novel effector helper T cell subsets in protective immunity

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The authors extend their appreciation to the deputyship for Research and Innovation, Ministry of Education in Saudi Arabia for funding this research work through the project number (436) .

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Copyright © 2020 Alfaleh, Alsaab, Mahmoud, Alkayyal, Jones, Mahler and Hashem. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.