The Antibody Society

the official website of the antibody society

An international non-profit supporting antibody-related research and development.

You are here: Home / Archives for Antibody discovery

Congratulations to Sir Greg Winter, Nobel laureate!

by

Sir Gregory P. Winter (MRC Laboratory of Molecular Biology, Cambridge, UK) was named Nobel Laureate by The Royal Swedish Academy of Sciences on October 3, 2018 “for the phage display of peptides and antibodies”. He shares the Nobel Prize in Chemistry with Frances H. Arnold (California Institute of Technology, CA, US) and George P. Smith (University of Missouri-Columbia, US). More information about the Nobel Prize can be found here.

Sir Greg Winter’s work on phage display and humanization of antibodies revolutionized the field and led to the approval of the first phage display-derived antibody, adalimumab (1). Although new methodologies have been used and implemented, phage display (2, 3) and humanization remain among the most important techniques used to drive antibody discovery and development of antibody-based therapeutics.

The Antibody Society is proud to have Sir Greg Winter among its scientific advisors.

References:
1. Guiding the Selection of Human Antibodies from Phage Display Repertoires to a Single Epitope of an Antigen
2. Phage display-derived human antibodies in clinical development and therapy
3. Drugs derived from phage display

Most read from mAbs issue 10.6

by

The Antibody Society is pleased and proud to be affiliated with mAbs, a multi-disciplinary journal dedicated to advancing the art and science of antibody research and development. We hope you enjoy these summaries based on the abstracts of the most read papers published in a recent issue. All the articles are open access; PDFs can be downloaded by following the links below.

Issue 10.6 (Aug/Sep 2018)

Antigen recognition by single-domain antibodies: structural latitudes and constraints. In this new review, Henry and MacKenzie comprehensively surveyed the evidence in support of the hypothesis that sdAbs may adopt paratope structures that predispose them to preferential recognition of recessed protein epitopes, but poor or non-recognition of protuberant epitopes and small molecules. They found some support for a global structural difference in the paratope shapes of sdAbs compared with those of conventional antibodies. Comparison of X-ray crystal structures of sdAbs and conventional antibodies in complex with cognate antigens showed that sdAbs and conventional antibodies bury similar solvent-exposed surface areas on proteins and form similar types of non-covalent interactions, although these are more concentrated in the compact sdAb paratope. Thus, the authors conclude that sdAbs likely have privileged access to distinct antigenic regions on proteins, but only owing to their small molecular size and not to general differences in molecular recognition mechanism. The evidence surrounding the purported inability of sdAbs to bind small molecules was less clear. The available data provide a structural framework for understanding the evolutionary emergence and function of autonomous heavy chain-only antibodies.

Biosimilars in oncology and inflammatory diseases: current and future considerations for clinicians in Latin America. Scheinberg et al. review the use of biosimilars in Latin America, which is complicated by the presence of “non-comparable biotherapeutics” (also known as “intended copies”) that have not been rigorously compared with the originator product. The authors discuss the current situation and the considerations for clinicians in Latin American countries, focusing on monoclonal antibody biosimilars relevant to oncology, rheumatology, gastroenterology, and dermatology.

Homology modeling and structure-based design improve hydrophobic interaction chromatography behavior of integrin binding antibodies. In this new report, Jetha et al. optimized a candidate integrin α11-binding mAb for developability using molecular modeling, rational design, and hydrophobic interaction chromatography (HIC). A homology model of the parental mAb Fv region was built, and this revealed hydrophobic patches on the surface of the complementarity-determining region loops. A series of 97 variants of the residues primarily responsible for the hydrophobic patches were expressed and their HIC retention times (RT) were measured. As intended, many of the computationally designed variants reduced the HIC RT compared to the parental mAb, and mutating residues that contributed most to hydrophobic patches had the greatest effect on HIC RT. A retrospective analysis was then performed where 3-dimentional protein property descriptors were evaluated for their ability to predict HIC RT using the current series of mAbs. The same descriptors were used to train a simple multi-parameter protein quantitative structure-property relationship model on this data, producing an improved correlation. This analysis was extended to recently published HIC data for 137 clinical mAb candidates as well as 31 adnectin variants, and the authors found that the surface area of hydrophobic patches averaged over a molecular dynamics sample consistently correlated to the experimental data across a diverse set of biotherapeutics.

Heterologous recombinant expression of non-originator NISTmAb. Kashi et al. describe the development and initial expression of an intended copy of the NISTmAb using three non-originator murine cell lines. The authors found that, without optimization and in culture flasks, all three cell lines produce approximately 100 mg mAb per liter of culture. SDS-PAGE, SEC, NMR spectroscopy, intact MS, and SPR were used to demonstrate that the products of all three cell lines embody quality attributes with a sufficient degree of sameness to the NISTmAb Reference Material 8671 to warrant further bioreactor studies, process improvements and optimization. The implications of the work with regard to pre-competitive innovation to support process design and feedback control, comparability and biosimilarity assessments, and process analytical technologies are discussed.

Like this post but not a member?

We encourage you to join the Society to take advantage of the substantial benefits of membership, including discounts on fees for selected KNect365, CHI, and Hanson Wade meetings, discounted subscriptions to Society-affiliated journals PEDS and mAbs (special subscription rate of US $84 online only access for Antibody Society members)  and access to information in the Members Only section of the website. In particular, we encourage members to take advantage of the discount on registration for Antibody Engineering & Therapeutics, which is the annual meeting of The Antibody Society traditionally held in San Diego in December. Membership is free for students, post-docs and employees of our corporate sponsors!

Post-translational Modification in Antibody Function

by

The Antibody Society is pleased to invite you to attend its annual Meeting, Antibody Engineering & Therapeutics, which will be held December 12-15, 2017, in San Diego, CA. We will be celebrating the 10th anniversary of the Society at the Society’s Special Session on Thursday December 14, 2017. In this session summary, Dennis R. Burton (The Scripps Research Institute) and Paul W.H.I. Parren (Leiden University Medical Center) discuss what you will learn in their session on post-translational modification in antibody function.

The critical importance of sequence variation in antibodies is well recognized. Sequence diversity in antibody variable domains is essential for specific antigen recognition while linkage to different constant domains leads to distinct Fc-mediated effector activities. Post-translational modifications (PTMs) of these domains provide an additional immune mechanism by which the binding and activity of antibodies can be modulated. PTMs vary from chain additions, such as N- and O-linked glycosylation, glycation, cysteinylation and sulfation; chain trimming, such as C-terminal lysine clipping; amino acid modifications such as cyclization (into a N-terminal pyroglutamic acid), deamidation, oxidation, isomerization and carbamylation; to disulfide scrambling of hinge region interchain disulfide bonds. Each antibody can therefore give rise to a myriad of distinct antibody molecules with large activity and potency differences. Although post-translational modifications of antibodies have been observed and studied for decades, we only now start to understand the full impact of this incredible microheterogeneity. PTMs have moved from being viewed as a mere nuisance to antibody manufacturing that requires controlling to a potential handle to modify and improve specific antibody functions.

In this session, we will hear about current state-of-the-art in PTM detection and novel insights into the role and modulation of PTMs in our immune system as well as the way in which we can exploit PTMs to make better (therapeutic) antibodies. The first and the second (after the break) part of our session will be initiated with lectures by renowned experts in their fields. Professor Albert Heck (Utrecht University) is a world-expert on the structural analysis of proteins by mass spectrometry. He received the Frank H. Field and Joe L. Franklin Award for outstanding achievement in mass spectrometry from the American Chemical Society and in 2017 he was received the NWO Spinoza Prize, which is the highest award in Dutch Science. Prof Heck will discuss how innovative and advanced mass spectrometry methods can be used to map antibody heterogeneity due to PTMs. Leendert Trouw (Leiden University Medical Center) will discuss the role of two amino acid modifications (citrullination and carbamylation) in the autoimmune disease rheumatoid arthritis (RA). On the one hand, the presence of antibodies against citrullinated or carbamylated proteins represents a prognostic marker for the disease. How antibodies recognize diverse antigens carrying these modifications is therefore an important area of study. Carbamylation of antibodies furthermore may also have functional consequences for antibody effector functions which will be highlighted. Professor Gerhard Krönke (University of Erlangen) will discuss how the PTM profile and inflammatory activity of autoantibodies in RA is regulated by TH17 helper T cells. His work gives us a novel insight into a mechanism by which the cellular immune system regulates the activity of antibodies and how its derailment may lead to the initiation of (autoimmune) disease.

After the break, Taia Wang (Stanford University School of Medicine) will discuss the diverse downstream proinflammatory, anti-inflammatory and immunomodulatory consequences of the engagement of type I and type II Fc receptors, which are influenced by the Fc’s amino acid sequence and the complex, biantennary Fc-associated N-linked glycan, in the context of infectious, autoimmune, and neoplastic disorders. Yingda Xu (Adimab) will bring us back to the importance of PTMS in manufacturing and control of therapeutic antibody production. He will show novel data on the identification of chemically labile sites in antibodies and how this information may be used in therapeutic antibody lead selection. Finally, Raiees Andrabi (The Scripps Research Institute) will discuss how sulfation of residues in the antibody binding site is critical for certain broadly neutralizing anti-HIV-1 antibodies targeting the envelope glycoprotein.

We hope that this session will convey the current interest and high excitement in antibody PTMs and will serve to promote further research into the importance and impact of PTM microheterogeneity for polyclonal antibody responses as well as for monoclonal antibody therapeutics.

 

Interested in attending the meeting? Learn more from this PDF, which includes all session summaries written by the chairpersons.

Society members can save 15% on the registration fee! Not a member? Please join!

Membership is free for students and employees of the Society’s corporate sponsors.

 

 

Novel antibody display, selection and screening technologies

by

The Antibody Society invites you to attend its annual meeting, Antibody Engineering & Therapeutics, on December 11-15, 2017 at the Manchester Grand Hyatt, San Diego, CA!

The session on “Novel antibody display, selection and screening technologies”, chaired by Andrew Bradbury, M.D., Ph.D. Research Scientist and Group Leader, Los Alamos National Laboratories; Chief Scientific Officer, Specifica, focusses on the new technologies expected to advance antibody library generation and selection in the future. Many of these reflect the rapidly growing role of next generation sequencing (NGS) in all aspects of in vitro antibody generation. Dr. Bradbury will discuss how NGS has enabled more informed discussions on antibody library sizes, and how traditional selection from antibody libraries does not address the full depth of possible positive antibodies. Tim Whitehead (Michigan State University) will discuss the power of NGS in protein engineering to analyze the outcomes of different selective pressures on antibody stability, affinity and function, and to use this information in antibody discovery programs, while Brandon DeKosky (The University of Kansas) will describe how the combination of cloning natural paired antibody responses to viruses with yeast display vectors provides insights into neutralizing HIV and Ebola responses. In addition to NGS, Benjamin Hackel (University of Minnesota) will describe the engineering of novel alternative novel yeast display vectors as applied to the development of novel small non-antibody scaffolds. James Wells (UCSF) will describe an innovative use of novel proteomic technologies involving phage display to both understand how cancer cells remodel their membrane proteomes, as well as to generate recombinant antibodies against them. Once potential therapeutic antibody leads have been identified, they need to be further developed before they can be used in the clinic. This involves understanding and overcoming fundamental challenges related to the design and selection of antibodies with high affinity, specificity, stability and solubility, a topic that will addressed by Peter Tessier (University of Michigan).

Interested in attending the meeting? Learn more from this PDF, which includes all session summaries written by the chairpersons.

Society members can save 15% on the registration fee! Not a member? Please join!

Membership is free for students and employees of the Society’s corporate sponsors.

 

IMMUNO-ONCOLOGY: CHECKPOINTS

by

The Antibody Society invites you to attend its annual meeting, Antibody Engineering & Therapeutics, on December 11-15, 2017 at the Manchester Grand Hyatt, San Diego, CA! In this summary, chairperson James Larrick, M.D., Ph.D., Managing Director and Chief Medical Officer, Panorama Research Institute and Velocity Pharmaceutical Development, discusses what you will learn at his session on immune-oncology checkpoints, which will be held on Friday December 15.

The management of cancer has dramatically changed over the past decade with the introduction of novel immunotherapies, chief among them inhibitors of checkpoint receptors — molecules whose function is to restrain the host immune response.  Antibodies inhibiting CTLA4 and PD1-PD-L1 have shown remarkable clinical benefit.  The field is evolving rapidly, with many clinical trials testing novel checkpoint inhibitors (e.g., anti-LAG3, anti-TIM3), alone, in combination, or with other targeted therapies. A sampling of novel approaches will be covered in this symposium.

This Friday morning (December 15, 2017) session will be led off by Mickey Hu (Panorama Institute of Molecular Medicine) who has developed a series of novel immunomodulatory drugs that suppress PD-L1 expression in tumor cells and inhibit the PD-L1/PD-1 checkpoint, resulting in the recruitment of natural killer (NK) cells into the tumor microenvironment that leads to tumor suppression. Efforts to combine immunomodulatory drugs with checkpoint blockades to overcome difficult-to-treat cancers with tolerable side effects will be described.

Clinical lead candidate antibodies often lack species cross-reactivity, necessitating the development of substitute antibodies for pre-clinical development in mice or monkeys. Next, Erik Hofman, (Argenx) will describe the use of the SIMPLE Antibody platform to generate functional human-mouse cross-reactive antibodies against several validated immune checkpoint proteins, including PD-1, VISTA and LAG-3.

Xin Lu (University of Notre Dame) will present data indicating that targeted therapy against myeloid-derived suppressor cells, using multikinase inhibitors such as cabozantinib and dactolisib, can synergize with immune checkpoint blockade antibodies (e.g., anti-CTLA4, anti-PD1) to eradicate metastatic castration-resistant prostate cancer.

A key feature of effective cancer immunotherapy relies on enhanced anti-tumor immune response and reduced suppressive effects. As natural cytokines are made to maintain a balance between activation and suppression, they are often unable to achieve desired therapeutic efficacy. Cheng-I Wang (Biomedical Sciences Institutes, ASTAR, Singapore) will describe a cytokine receptor agonist antibody that mimics IL-2’s immune stimulatory effects on CD8 T cells with minimal Treg activation.

Cow antibodies have unusually long CDR3 regions. Vaughn Smider (The Scripps Research Institute) has characterized the genetic and structural properties of these antibodies, and has identified novel antibodies against HIV and exhausted T-cell targets utilizing this approach.

The final speaker, Sarah Crome, (Princess Margaret Cancer Centre, University Health Network, Canada) will describe efforts to characterize a unique innate lymphoid cell (ILC) population that suppresses the expansion and function of tumor-associated T cells, and is associated with early recurrence in high-grade cancer. This regulatory ILC population has properties that overlap with NK cells and other defined ILCs, yet can be differentiated by a distinct gene expression signature. Studies defining molecular interactions that control regulatory ILC function and ways to target this population to enhance immunotherapy will be presented.

Interested in attending the meeting? Society members can save 15% on the registration fee!

Not a member? Please join!

Membership is free for students and employees of the Society’s corporate sponsors.