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Post-translational Modification in Antibody Function

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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.

 

 

Antibody-based innovations in the tumor microenvironment

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Please join us at the Society’s annual meeting, Antibody Engineering & Therapeutics on December 11-15, 2017 at the Manchester Grand Hyatt, San Diego, CA!

Clinical successes of the checkpoint modulators have revived the ambition to cure cancer by manipulation of the tumor microenvironment, or by unleashing or even priming (novel) adaptive immune responses. Hence, understanding the tumor microenvironment is an increasingly vital theme in the field of antibody-based therapeutics. This theme is excitingly addressed during two sessions “Antibody-based innovations in the tumor microenvironment 1 & 2”, jointly chaired by Kerry Chester and Janine Schuurman, which will be held on Thursday December 14, 2017. The sessions’ antibody-focused complementary topics are intended to expand knowledge at the cutting edge of the tumor microenvironment field, and are anticipated to boost lively discussions and stimulate new lines of thinking.

Antibody-based innovations in the tumor microenvironment (I, morning session)

Chairwomen: Kerry Chester, Professor of Molecular Medicine, UCL Cancer Institute, University College London, United Kingdom, and Janine Schuurman, Vice President Research, Genmab, Utrecht, The Netherlands

The sessions will open with a presentation by John Anderson (UCL) who will examine current thinking on immune evasion as a hallmark of cancer and why the solid tumor microenvironment is particularly hostile to immunotherapeutic function of effector cells. He will explain that, unlike adult cancers, pediatric cancers generally arise with few mutations and tend to be insensitive to existing immune modulators. Treatment approaches designed to target cell surface antigens in combination with agents to reverse immune evasion are likely to be required for this special group of patients.  New data will be presented in support of this hypothesis.

Syd Johnson (MacroGenics) will then share data on how to achieve co-stimulation of immune cells specifically within the tumor microenvironment using bispecific Dual-Affinity Re-Targeting (DART) and TRIDENT antibodies that bind both tumor-specific antigens and T-cell costimulatory molecules. Importantly, tumor binding is required to trigger costimulation. The talk will be illustrated with a case study showing how to achieve optimal tumor dependent T cell engagement by varying the relative position and valence of each antibody binding site in the molecule; manufacturability, stability and PK will also be addressed.

Natalia Arenas Ramirez (University Hospital Zurich) will then present an elegant antibody-based solution to problems associated with IL-2 immunotherapy.  IL2 binding to the IL-2 receptor α (CD25) subunit leads to unwanted side effects, including stimulation of immunosuppressive Tregs.  The talk will describe development of NARA1, an anti-IL-2 monoclonal antibody that acts as a high-affinity CD25 mimic, preferentially stimulating CD8+ cells while keeping the Tregs low.  Potent antitumor responses are achieved.

After the Networking Break, Volker Schellenberger (Amunix) will present an interesting approach to achieving activation in the tumor environment using bispecific T-cell engagers based on the ProTIA (Protease Triggered Immune Activator) platform. ProTIA combines tumor binding, proteolytic activation and polymer targeting due to an attached XTEN. Amunix’ lead molecule, AMX-168, is expected to enter clinical development in 2018.

Next, Shautong Song (Icell Kealex Therapeutics) will showcase an innovative way to focus treatment within the tumor microenvironment via bi-specific T-cell engager-armed oncolytic vaccinia virus. The treatment has several modes of action: vaccinia virus can directly lyse tumor cells and bi-specific T-cell engagement directs T-cells to kill both tumor and by-stander cells. In addition, T-cell engagement promotes T-cell infiltration into tumors and the cytokines released upon activation create a pro-inflammatory microenvironment that inhibits tumor growth. The strategy provides a sophisticated means of reducing systemic side effects associated with bi-specific T-cell engagers.

To complete the morning session, Dane Wittrup (Massachusetts Institute of Technology) will explore how classical monoclonal anti-tumor antibodies, such as anti-HER2 or anti-CD20, synergize with immune oncology antibodies, such as anti-PD-1. This is achieved not only by delivery of  tumor debris to antigen presenting cells for cross presentation, but also by creating a more inflammatory state and a localized cytokine storm in the tumor microenvironment.

Antibody-based innovations in the tumor microenvironment (II, afternoon session)

Chairwomen: Janine Schuurman, Vice President Research, Genmab, Utrecht, The Netherlands and Kerry Chester, Professor of Molecular Medicine, UCL Cancer Institute, University College London, United Kingdom

The afternoon session opens with a presentation centering on adaptive immune responses boosted by therapeutic cancer vaccines using RNA. Sebastian Kreiter (BioNTech) will focus on preclinical and clinical efforts to use personalized neoepitope vaccines in combination with immunomodulatory antibodies.

Edward Roberts (UCSF) will follow with a complementary line of thinking harnessing long term anti-tumor therapeutic effects. He will share data, including imaging data, to give us insights in the requirements for effective tumor antigen trafficking to the lymph nodes by the dendritic cells. These understandings may stimulate ideas for effective T cell priming approaches.

The TNFR super family (TNFR-SF) is a highly represented target class in the immunomodulatory targets space. Clustering is an important prerequisite for agonistic effects of antibodies against these targets. Nick Wilson (Agenus) will share emerging data on the role of antibody Fc and Fc-receptor biology to optimize the agonistic properties of antibodies against this target class.

Daratumumab, an anti-CD38 antibody that is approved for the treatment of relapsed / refractory myeloma, has multiple mechanisms of actions. Apart from rapid tumor cell reduction and direct anti-tumor effects, daratumumab significantly reduces CD38+ immune suppressive cells in the tumor microenvironment. Kate Sasser (Genmab) will focus on the immune modulatory activity of this antibody substantiated with data from in vitro evaluations and clinical studies.

Bispecific antibodies directed against both CD3and a tumor target can engage non-tumor-specific T cells, resulting in effective tumor-specific cell killing. Dirk Hose (Heidelberg University) will share data on a bispecific IgG-based molecule that targets CD3 and the B-cell maturation antigen (BCMA), which has been implicated in multiple myeloma. This presentation will cover the generation of this molecule and include early stage clinical learnings.

Anti-CD3 bispecifics can have severe toxicity profiles related to the expression profile of the tumor antigen. The last speaker of this full-day session on the tumor microenvironment will share data on the improvement of the therapeutic index of an anti-CD3 bispecific antibody also directed against a widely expressed antigen, epidermal growth factor receptor (EGFR). In this case study, Leila Boustany, (CytomX) will present the localization of the activity to the tumor microenvironment, which is accomplished by an engineering approach, i.e., a protease activatable EGFRxCD3 bispecific exploiting the protease activity present in the tumor microenvironment.

We anticipate that these complementary scientific insights focusing around antibody-based innovations in the tumor microenvironment will excite us all and inspire our forward-looking capabilities.

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 engineering strategies to enhance antibody functions

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Please join us at the Society’s annual meeting, Antibody Engineering & Therapeutics, on December 11-15, 2017 at the Manchester Grand Hyatt, San Diego, CA! Here, Paul J. Carter, Ph.D., Senior Director and Staff Scientist, Antibody Engineering, Genentech, discusses what you will learn in his session on novel engineering strategies to enhance antibody functions, which will be held on Friday December 15, 2017.

A recurring theme with this conference since it began in the early 1990s has been the presentation of new antibody engineering technologies and their application to the design of antibodies for specific clinical applications. True to this tradition, this session will showcase a broad range of different antibody platform technologies for improving existing antibody properties or engineering antibodies with brand new capabilities. Antibody technologies to be highlighted include bispecific antibodies in many different formats, PEGylation, glyco-engineering and engineering of isoelectric point (pI).

Greg Lazar (Genentech) will present on agonizing the TNFR superfamily independent of FcgR-mediated cross-linking using multiple antibody technology platforms. This talk will highlight in vitro and in vivo proof-of-concept data. Taichi Kuramochi (Chugai Pharmabody Research) will provide a case study on pI engineering of an antibody variable domains and constant regions to enhance the potency of pH-dependent antigen binding antibody. Gestur Vidarsson (Sanquin Research) will describe how the natural glycans of antibodies can be tailored to increase ADCC and/or CDC activities. For example, combining hypergalactosylation with afucosylation increases the potency of ADCC activity beyond that achieved by afucosylation alone.

After the networking break, Martin Steegmaier (Roche Innovation Center Munich) will discuss applications of CrossMAbs in bivalent (1+1), trivalent (2+1) and tetravalent (2+2) formats for cancer immunotherapy and the use of novel targeting approaches for neurological diseases. Additionally, bispecific antibodies in DutaFab format for ophthalmologic diseases will be described.  Qing Li (Medimmune) will demonstrate tumor uptake of a PEGylated antibody fragment. Specifically, this presentation will focus on investigation of the correlation between hydrodynamic size, pharmacokinetic parameters and tumor uptake of a PEGylated diabody. Kartik Chandran (Albert Einstein College of Medicine) will close the session by presenting a bispecific antibody “Trojan horse” approach for broad protection against ebolaviruses. One arm of the bispecific antibody binds a conserved epitope on ebolavirus glycoprotein. After internalization of the virus/antibody complex into cells and trafficking to late endosomes, the second arm of the bispecific blocks infection by binding to the viral entry receptor, NPC1.

Interested in attending the meeting? Society members can save 15% on the registration fee! Contact us at membership@antibodysociety.org for the code.

Not a member? Please join!

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

The Antibody Society joins FOCIS!

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We are pleased to announce that The Antibody Society is now a Member Society of the Federation of Clinical Immunology Societies (FOCIS), which exists to improve human health through immunology by fostering interdisciplinary approaches to both understand and treat immune-based diseases. By joining FOCIS as a Member Society, our network has expanded to include over 60,000 clinicians and basic researchers dedicated to a cross-disciplinary approach to immunologic disease.

Information about Member Society and Individual Membership benefits, education opportunities, FOCIS publications and the FOCIS Member Society Roster can be found here. We look forward to working with FOCIS to achieve the goals shared by our organizations.

Engineering and Application of Therapeutic Antibodies for Neurodegenerative Diseases

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The Antibody Society is pleased to invite you to attend its annual Meeting, Antibody Engineering & Therapeutics, which will be held December 11-15, 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 session previews that will be posted during September-November, the session chairs discuss the relevance of their topics to current and future antibody therapeutics development.

The nervous system is especially vulnerable to the disrupted proteostasis and accumulations of toxic forms of proteins that occur naturally with aging, and/or as a result of genetic and environmental risk factors. As our overall populations age, these disorders loom as a massive public health problem due to the level of care required for affected individuals. Antibodies, with their inherent specificity for protein isoforms, will become increasingly critical as therapeutics and diagnostics. Engineering and Application of Therapeutic Antibodies for Neurodegenerative Diseases, which will be presented on Wed. morning, Dec. 13, has been organized by Anne Messer (Neural Stem Cell Institute/ Univ. Albany), Cynthia Lemere (Brigham & Women’s Hospital/Harvard Medical School) and James Huston (Huston BioConsulting, LLC). The speakers in this session will present a range of approaches for Alzheimer’s and related dementias, Parkinson’s, and ALS/motor neuron disease, including notes on the extent to which there can be overlaps among these and other protein misfolding diseases.

The talks in the first half of the session will focus on an important target in Alzheimer’s, amyloid beta (Aβ). Isabelle Aubert (University of Toronto) will present the opening talk, “Delivery of Antibodies across the Blood-brain Barrier Using MRI-guided Focused Ultrasound,” including promising data on functional improvement after treatments with anti- Aβ antibodies. [This talk also represents a continuation of the theme of approaches to blood brain barrier permeability in the keynote talk by William Pardridge (UCLA), and a session talk by Jasi Atwal (Genentech), on Tuesday, Dec. 13.] Next in our session, Christoph Hock (University of Zurich) will present “Antibody Therapy for Alzheimer’s Disease – Key Challenges.” These challenges include targeting the most relevant Aβ species, establishing a consistent dose-response, selecting the right timing and duration of the intervention, demonstrating a clinical / biomarker correlation and managing amyloid related imaging abnormalities (ARIA E/H). 
Michael Sierks (Arizona State University) will present his cutting-edge engineering and catalytic antibody approaches to preventing formation of the toxic species in “Altering APP Processing with a Proteolytic Diabody.”

The second half of the session covers immunotherapies for multi-faceted neurodegenerations. 
Laura Ranum (University of Florida) uses a mouse model of a human mutation that can lead to motor, cognitive, and/or anxiety symptoms due to accumulation of novel mutant proteins. These may be less rare than we currently appreciate. In the talk “Towards Development of Antibody Therapy for C9orf72 ALS/FTD”, Prof. Ranum will present preclinical studies of peripheral delivery of human antibodies. 
Peter Davies (Feinstein Institute for Medical Research, NY) has developed very critical monoclonal antibodies to Tau, which is a major player in neurofibrillary tangles of Alzheimer’s disease, and the accumulating protein in hereditary and injury-induced dementias. “Treatment of Neuronal Pathology with Monoclonal Antibodies” discusses moving these valuable diagnostic and research tools into the therapeutic realm. The final talk, by Eliezer Masliah (National Institutes of Aging, NIH), is “Combinatorial Immunotherapeutic Approaches for Synucleinopathies of the Aging Population.” This innovative approach harnesses both adaptive and innate immune processes that will be critical for dealing with Parkinsons and several other aging diseases that accumulate alpha-synuclein.

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.