Antibodies to watch in 2020

Kaplon, Hélène; Muralidharan, Mrinalini; Schneider, Zita; Reichert, Janice M.

doi:10.1080/19420862.2019.1703531

Cited by 413 publications

(306 citation statements)

References 37 publications

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“…Leronlimab (previously known as PRO140) is a humanized IgG4 targeting CCR5 which CytoDyn is progressing through multiple stages of clinical development for a variety of diseases, namely CCR5-tropic HIV infection, metastatic TNBC, metastatic colorectal cancer, nonalcoholic steatohepatitis (NASH), and graft-versus-host disease (GvHD) with a variety of preclinical studies ongoing in an oncology setting [66].…”

Section: Leronlimabmentioning

confidence: 99%

A review of antibody-based therapeutics targeting G protein-coupled receptors: an update

Hutchings

2020

Expert Opinion on Biological Therapy

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Section: Leronlimabmentioning

confidence: 99%

A review of antibody-based therapeutics targeting G protein-coupled receptors: an update

Hutchings

2020

Expert Opinion on Biological Therapy

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“…Since then, mAbs have become one of the most clinically successful therapeutic modalities across a diverse array of diseases. They have revolutionized the treatment of chronic inflammatory diseases and of some cancers including otherwise incurable malignancies 1. They are commercially important and in 2017, five mAbs collectively grossed $45.6 billion in sales, placing them in the top ten drugs globally 2.…”

Section: Introductionmentioning

confidence: 99%

Harnessing the immune system via FcγR function in immune therapy: a pathway to next‐gen mAbs

et al. 2020

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The human fragment crystallizable (Fc)c receptor (R) interacts with antigencomplexed immunoglobulin (Ig)G ligands to both activate and modulate a powerful network of inflammatory host-protective effector functions that are key to the normal physiology of immune resistance to pathogens. More than 100 therapeutic monoclonal antibodies (mAbs) are approved or in late stage clinical trials, many of which harness the potent FccR-mediated effector systems to varying degrees. This is most evident for antibodies targeting cancer cells inducing antibody-dependent killing or phagocytosis but is also true to some degree for the mAbs that neutralize or remove small macromolecules such as cytokines or other Igs. The use of mAb therapeutics has also revealed a "scaffolding" role for FccR which, in different contexts, may either underpin the therapeutic mAb action such as immune agonism or trigger catastrophic adverse effects. The still unmet therapeutic need in many cancers, inflammatory diseases or emerging infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires increased effort on the development of improved and novel mAbs. A more mature appreciation of the immunobiology of individual FccR function and the complexity of the relationships between FccRs and antibodies is fueling efforts to develop more potent "next-gen" therapeutic antibodies. Such development strategies now include focused glycan or protein engineering of the Fc to increase affinity and/or tailor specificity for selective engagement of individual activating FccRs or the inhibitory FccRIIb or alternatively, for the ablation of FccR interaction altogether. This review touches on recent aspects of FccR and IgG immunobiology and its relationship with the present and future actions of therapeutic mAbs.

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“…Antibody therapeutics are one of the most important classes of drugs. By the end of 2019, 90 monoclonal antibody drugs covering immune disease, infection disease, cardiovascular disease, cancer and others had been approved in the U.S. and Europe [1], accounting for a projected $150B [2]. While at one time rodent antibodies were developed for human use, this was followed by a long period of humanized antibodies, which over the last two decades has shifted to entirely human discovery platforms like phage [3] and yeast display [4] or by immunization of rodents with human germline repertoires [5].…”

Section: Introductionmentioning

confidence: 99%

Rapid and robust antibody Fab fragment crystallization utilizing edge-to-edge beta-sheet packing

Atwell

Lieu

Antonysamy

et al. 2020

Preprint

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20Antibody therapeutics are one of the most important classes of drugs. Antibody structures 21 have become an integral part of predicting the behavior of potential therapeutics, either directly or 22 as the basis of modeling. Structures of Fab:antigen complexes have even greater value. While the 23 crystallization and structure determination of Fabs is easy relative to many other protein classes, 24 especially membrane proteins, broad screening and optimization of crystalline hits is still 25 necessary. Through a comprehensive review of rabbit Fab crystal contacts and their 26 incompatibility with human Fab structures, we identified a small secondary structural element 27 from the rabbit light chain constant domain potentially responsible for hindering the crystallization 28 of human Fabs. Upon replacing the human kappa constant domain FG loop (HQGLSSP) with the 29 two residue shorter rabbit loop (QGTTS), we dramatically improved the crystallization of human 30 Fabs and Fab:antigen complexes. Our design, which we call "Crystal Kappa", enables rapid 31 crystallization of human fabs and fab complexes in a broad range of conditions, with less material 32 in smaller screens or from dilute solutions. 33 Abbreviations 34 CDR Complementarity determining region 35 CFC Column fraction crystallization 36 CK Crystal Kappa 37 GITR Glucocorticoid-Induced TNFR-Related Protein 38 TIGIT T-cell immunoreceptor with Ig and ITIM domains 39 LC Light Chain 40 HC Heavy Chain 41 CH1 Constant Heavy Domain 1 42 Ckappa Constant Kappa Domain 43 Fv Antibody variable domain fragment 44 45 Introduction 46 Antibody therapeutics are one of the most important classes of drugs. By the end of 2019, 47 90 monoclonal antibody drugs covering immune disease, infection disease, cardiovascular disease, 48 cancer and others had been approved in the U.S. and Europe [1], accounting for a projected $150B 49 [2]. While at one time rodent antibodies were developed for human use, this was followed by a 50 long period of humanized antibodies, which over the last two decades has shifted to entirely human 51 discovery platforms like phage [3] and yeast display [4] or by immunization of rodents with human 52 germline repertoires [5]. In these platforms engineering is not necessary for humanization but 53 continues to be used to address other issues: affinity, cross-reactivity, post translational 54 modifications, hydrophobicity, electrostatics, viscosity, and immunogenicity. Furthermore, 55 characterization of antibodies continues to become more sophisticated, especially as new antibody 56 derived formats are developed like antibody drug conjugates and bispecific antibodies [6]. 57 Modeling of antibody structures has become an integral part of predicting the behavior of 58 potential therapeutics, especially for properties such as hydrophobicity, stability, charge/dipole 59 moments and deamidation propensity [7]. This modeling is typically based on the publicly 60 available crystal structures with the most similar CDR sequences. Due to the difficulty of modeling 61 ...

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Antibodies to watch in 2020

Cited by 413 publications

References 37 publications

A review of antibody-based therapeutics targeting G protein-coupled receptors: an update

A review of antibody-based therapeutics targeting G protein-coupled receptors: an update

Harnessing the immune system via FcγR function in immune therapy: a pathway to next‐gen mAbs

Rapid and robust antibody Fab fragment crystallization utilizing edge-to-edge beta-sheet packing

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