The Antibody Society

the official website of the antibody society

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

Efgartigimod: A Novel FcRn Antagonist in the Treatment of Autoimmune Diseases

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Summary written by Alicia Chenoweth, PhD, King’s College London

Antibody Engineering & Therapeutics, held in December 2022, offered many opportunities to hear exciting and informative presentations by experts in the field, including Dr. Hans de Haard, Chief Scientific Officer at argenx.

Dr. de Haard’s talk, Efgartigimod: A Novel FcRn Antagonist in the Treatment of Autoimmune Diseases, detailed the mechanism of action and clinical trial results of the FcRn antagonist efgartigimod. Efgartigimod is a human IgG1 Fc fragment with five “Abdeg” mutations (M252Y, S254T, T256E, H433K, N434F) to increase its affinity for FcRn at both low pH and neutral pH (1,2). It is designed to outcompete the binding of serum IgG for FcRn, leading to degradation of the unbound IgG and recycling of efgartigimod back to the surface of the cell to be released back into circulation.

Dr. de Haard discussed the findings of a recent publication in which the biochemical, structural, and in vivo properties of efgartigimod and a full-length antibody counterpart containing the same Abdeg mutations were compared (3). Crystallographic studies of FcRn in complex with the full-length antibody demonstrated that the antigen-binding fragment projects towards the membrane, leading to a potential steric clash hindering binding. This hypothesis was confirmed using a bioassay measuring receptor occupancy, showing that efgartigimod gave a better FcRn occupancy and had improved uptake compared to the full-length antibody. Furthermore, in cynomolgus monkeys, the Fc fragment gave a much faster clearance of tracer antibody and a more potent pharmacodynamic effect compared to full-length antibody. Thus, the Fc fragment was determined to be the better performing FcRn antagonist over the full-length antibody due to improved blocking of IgG recycling in vitro and the more potent PD effect in vivo.

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Engineering of human sialidase Neu2 as novel immunotherapy

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Post written by Czeslaw Radziejewski, Ph.D.

Antibody Engineering & Therapeutics, held in December 2022, offered many opportunities to hear exciting and informative presentations by experts in the field, including Li Peng, Ph.D., who discussed “Engineering of human Sialidase Neu2 as Novel Immunotherapy for Degrading Immunosuppressive Sialoglycans to Enhance Antitumor T-Cell Immunity”.

Glycans are the most abundant structures on the cell surface. They are involved in cell communication with immune cells, and abnormal glycans can cause immune dysfunction in cancer and inflammatory diseases. Glycans typically terminate in sialic acid, but in cancer cells, sialic acid is present at a much higher abundance. The most common sialic acid in humans is N-acetylneuraminic acid, which plays a crucial role in numerous intercellular interactions, including with immune cells in the extracellular matrix, epithelial cells, and antibodies. Many studies have shown that sialoglycans are immunosuppressive and that high levels of surface sialoglycans are linked with poor outcomes in many tumor types. Hypersialylation of the surface of cancer cells makes these cells prime ligands for sialic acid-binding immunoglobulin-type lectins (Siglecs), which are found on the surface of immune cells. Once bound to sialylated glycans, Siglecs promote immunosuppressive signaling, thus conferring protection on the tumor cell. There are 15 human Siglecs. In addition, CD-28 is also known to bind sialoglycans. Most immune cells express more than one Siglec.

In her plenary lecture at the 2022 Antibody Engineering & Therapeutics conference, Professor Carolyn Bertozzi, outlined opportunities for the development of cancer treatments based on understanding the cell-surface glycome. She favored degrading sialoglycans with the enzyme sialidase to eliminate the immunosuppression promoted by Siglecs. As proof of concept, a fusion protein was created in Bertozzi’s lab using click chemistry, linking bacterial sialidase to the C-terminus of trastuzumab. The conjugate was tested in a mouse model of a trastuzumab-resistant HER2+ breast cancer model, and the results showed that the treatment essentially abrogated tumor growth. Based on these promising findings, Bertozzi cofounded Palleon Pharmaceuticals to explore sialidase-based biotherapies for cancer treatment.

At the conference, Dr. Li Peng, Chief Scientific Officer of Palleon Pharmaceuticals, presented the company’s progress in moving this concept toward the clinic. Palleon created a set of proprietary Siglec-based reagents for immunohistological hypersialylation detection and probing its role in immunotherapy resistance. Using such reagents, Palleon examined tissues from metastatic melanoma patients treated with PD1 blockade and showed that patients with a high level of sialylation fared much worse than patients with lower levels of sialoglycans. Following Bertozzi’s line of reasoning, the company pursued a strategy of using the enzymatic functionality of sialidase to remove excessive cell-surface sialylation. To translate this idea into a human therapeutic, Palleon decided to use a genetic fusion of sialidase with human Fc.

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The Antibody Society announces the election of new Directors and Officers

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The Antibody Society, Inc., an international non-profit trade association focused on the advancement of antibody research and development, is pleased to announce the election of Drs. Alexey Lugovskoy and John Desjarlais to the Board of Directors, the election of Peter Ros as the Society’s Treasurer, and the promotion of Janice Reichert to Chief Operating Officer. They assumed these roles on January 1, 2023.

These Directors and Officers bring substantial experience and expertise to their new roles. Drs. Lugovskoy and Desjarlais have each made seminal contributions to the field of antibody discovery and development and have critical experience with building successful collaborations, partnerships and alliances. Peter Ros brings finance and accounting expertise and over twenty years of financial experience within biotech business operations, while Dr. Reichert brings expertise in business intelligence and seven years of experience as the Society’s Executive Director to her new role as COO.

Prof. Paul Parren, Chair of the Society’s Board of Directors remarked “I look forward to working with Alex, John, Peter, and Janice in their new roles. Their valued contributions and expertise will enable us to further professionalize the Society and increase its ability to support the field of therapeutic antibody drug development by stimulating the interchange of ideas with opinion leaders and policy makers.”

Alexey Lugovskoy, Ph.D., President and CEO of Diagonal Therapeutics and Entrepreneur in Residence at Atlas Venture.

During his 20+ year career in biotechnology, Dr. Lugovskoy guided multiple oncology, autoimmunity, and rare disease programs into the clinic serving as COO of Dragonfly Therapeutics, CDO of Morphic Therapeutic, Vice President of Therapeutics at Merrimack Pharmaceuticals, and Associate Director of Drug Discovery at Biogen. He is an author of over 100 patents and manuscripts, and an Associate Editor of mAbs. He received an Advanced Certificate for Executives in Management, Innovation and Technology from MIT Sloan School of Management, a Ph.D. in Biophysics from Harvard University, an M.Sc. in Molecular Biophysics, and a B.Sc. in Mathematics and Physics from the Moscow Institute of Physics and Technology.

John Desjarlais, Ph.D., Chief Scientific Officer, Xencor

Dr. Desjarlais is an internationally recognized leader in the field of antibody and protein engineering for the creation of novel therapeutic modalities to treat a variety of diseases, including autoimmune diseases and cancer. Dr. Desjarlais oversees all of Xencor’s discovery research and preclinical activities, from project conception and candidate generation through preclinical proof-of-concept and early development.  Prior to Xencor, Dr. Desjarlais was an Assistant Professor of Chemistry at Penn State University (1997-2001), where he developed and tested computational methods for the de novo design of proteins.  He began his work in the field of protein design as a Jane Coffin Childs Fellow at U.C. Berkeley.  Dr. Desjarlais holds a Ph.D. in Biophysics from the Johns Hopkins University and a B.S. degree in Physics from the University of Massachusetts, Amherst.

Peter Ros, RA, Vice President of Finance at Lava Therapeutics

Mr. Ros serves as Vice President of Finance at Lava Therapeutics, a biotechnology company focused on developing bispecific gamma-delta T cell engagers to transform cancer therapy, since January 2020. Prior to joining Lava Therapeutics, he served in various roles at Genmab, including as Senior Director of Accounting and Finance from October 2018 to December 2019, Senior Director of Finance and Accounting, R&D Operations from July 2015 to September 2018 and (Senior) Director of Finance from November 2001 to June 2015. Mr. Ros also served as an Accountant at PricewaterhouseCoopers from September 1993 to April 1999. He received a RA title in accountancy from VU Amsterdam (1998) and his HEAO RA degree in accountancy from Windesheim University (1993).

Janice Reichert, Ph.D., Chief Operating Officer of The Antibody Society

Dr. Reichert is an internationally-recognized expert in the development of antibody therapeutics. She served as the Executive Director of The Antibody Society from 2016 to 2022. Dr. Reichert is Founder and Editor-in-Chief of mAbs, a Society-affiliated journal that focuses on topics relevant to antibody research and development. Dr. Reichert has published extensively on development trends for antibody therapeutics, and she has presented her research results as an invited speaker at conferences held worldwide. Dr. Reichert received her PhD in Chemistry from the University of Pennsylvania and did her post-doctoral training at Harvard Medical School.

About The Antibody Society

The Antibody Society, Inc. is an international non-profit trade association representing individuals and organizations involved in antibody research and development. The Society is an authoritative source of information about antibody therapeutics development, which is disseminated via our website, presentations and publications. In addition, the Society organizes conferences and webinars on antibody research and development and related topics. The Society also serves as the home for the Adaptive Immune Receptor Repertoire Community, which focuses on developing standards and protocols for curating, analyzing and sharing antibody B and T cell receptors. As a business association, the Society can engage with government and international agencies such as the World Health Organization to discuss topics that are important to the antibody community, such as international naming conventions. To keep up to date with antibody-related news, follow us on LinkedIn and Twitter.

AIRR Data Commons and iReceptor Science Gateway Start Major Collaboration with Type-1 Diabetes Researchers

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The AIRR Community is pleased to announce the addition of a new Type 1 Diabetes (T1D) focused repository in the AIRR Data Commons. This is a collaboration between the iReceptor team (Simon Fraser University), The Sugar Science group, the Aaron Michels Lab (University of Colorado), and the Todd Brusko Lab (University of Florida) among others. This repository contains the first fully HLA/MHC genotyped study that adheres to the the AIRR v1.4 MHC genotype standard, with over 62 million annotated sequences from 359 repertoires from the Mitchell et al. longitudinal study of TCR repertoires (TRB locus) in children who progressed to T1D. This new T1D AIRR-seq data is searchable through the iReceptor Gateway and there is of course more T1D data to come from this collaboration. We encourage the community to share this valuable type of data!

FDA approves Leqembi (lecanemab-irmb) for the treatment of Alzheimer’s disease

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On January 6, 2023, the U.S. Food and Drug Administration approved Leqembi (lecanemab-irmb) via the Accelerated Approval pathway for the treatment of Alzheimer’s disease. The labeling states that treatment with Leqembi should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was studied in clinical trials. The approved dose of lecanemab is 10 milligram/kilogram every two weeks.

Lecanemab (BAN2401) is a humanized anti-amyloid beta protofibril IgG1k antibody initially developed by BioArctic Neuroscience. BAN2401 was licensed to Eisai in a collaboration agreement, allowing the jointly development of lecanemab as a treatment for Alzheimer disease (AD). Under an agreement with Biogen, Eisai and Biogen co-commercialize and co-promote lecanemab.

The accelerated approval was supported by data from Study 201 (NCT01767311), which assessed the clinical efficacy of lecanemab at multiple doses (2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, 10 mg/kg biweekly) or placebo and explored the dose response of lecanemab using a composite clinical score (ADCOMS) in 856 patients with mild cognitive impairment due to AD and mild AD with confirmed presence of amyloid pathology. Patients receiving the treatment had significant dose- and time-dependent reduction of amyloid beta plaque, with patients receiving the approved dose of lecanemab, 10 milligram/kilogram every two weeks, having a statistically significant reduction in brain amyloid plaque from baseline to Week 79 compared to the placebo arm, which had no reduction of amyloid beta plaque.

Lecanemab is also being evaluated in the Clarity AD Phase 3 study (NCT03887455), which is designed to evaluate the efficacy, long-term safety, and tolerability of 10 mg/kg IV lecanemab administered every 2 weeks in 1795 patients with early AD. The primary outcome measurement was the change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) at 18 months of treatment. In September 2022, Eisai Co and Biogen Inc announced positive topline results from Clarity AD Phase 3 trial where lecanemab met the primary endpoint by reducing by 27% the clinical decline on the CDR-SB compared with placebo at 18 months. All key secondary endpoints were also met. Based on results of the study, Eisai may file for traditional approval in the US and for marketing authorization applications in Japan and Europe.