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Biological Impact of Fc Receptor Engagement

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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! In this summary, session organizers Trudi Veldman (Senior Director Biologics, AbbVie Bioresearch Center) and Chung-Ming Hsieh (Executive Director, Biologics Discovery Boston, Merck & Co.) discuss what you will learn at their session ‘Biological Impact of Fc Receptor Engagement’, which will be chaired by Chung-Ming Hsieh on Thursday December 14.

Antibodies are both binding proteins to their cognate targets and bridging molecules to downstream biological pathways via interaction with the various Fc receptors (e.g., FcγR and FcRn), complement, and lectins.  While our efforts in understanding the biology of therapeutic antibodies are often initially focused on the variable domain and target engagement, e.g., binding kinetics, potency, epitopes, it is crucial that we also gain understanding of the biology of the constant region of a therapeutic antibody and its impact on efficacy and safety.

This session aims to strengthen our current understandings on the biological impact of Fc receptor engagement.  The first presentation by Kenta Haraya (Chugai) will discuss the generation and characterization of a novel IgG1 Fc variant with optimized binding to FcRn that does not have increased binding by rheumatoid factors.  This Fc variant has been incorporated into a recycling antibody being developed for complement-mediated diseases.

The next three presentations will focus on the impact of FcγR engagement on antitumor activities of protein therapeutics.  Rony Dahan (Rockefeller) will present the finding that the antitumor activity of a human CD40 agonistic antibody is dependent on FcγRIIb engagement and is inhibited by FcγRIIa engagement, highlighting the importance of Fc domain optimization for improved efficacy.  Moving beyond antibodies, Daniel Christ (Garvan Institute of Medical Research) will present data indicating that the potent antitumor activity of interleukin-2-Fc fusion protein requires Fc-mediated depletion of regulatory T-cells.  Lastly, Frederick Arce Vargas (University College London Cancer Institute) will present the depletion of tumor-infiltrating regulatory T cells by an Fc-optimized anti-CD25 in synergy with PD-1 blockade to eradicate established tumors.

The field also continues to make progress in engineering Fc for modulating antibody effector functions, FcγR or complement engagement, and circulating half-life.  To this end, James Ernst (Genentech) will present effector function-attenuating mutations that maintain antibody stability and reduce toxicity.  George Georgiou (University of Texas at Austin) will present a set of novel engineered Fcs for half-life extension and for highly selective engagement of a single FcγR or C1q.

The full agenda for the meeting can be found here.

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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.

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

Innovating Antibody Therapeutics

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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! On Friday, December 15, Paul W.H.I. Parren, Ph.D., Professor, Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, and William R. Strohl, Ph.D., President of BiStro Biotech Consulting, LLC, are co-chairing a session on Innovating Antibody Therapeutics.

In today’s highly competitive therapeutic antibody environment, continued innovation is key to success.  This session highlights a number of innovative approaches to antibody discovery, engineering, and analysis.  The first presentation, given by Chris Bailey-Kellogg, Ph.D., Professor of Computer Science, Dartmouth University, explores the use of a method called EpiScope which combines a sophisticated computer algorithm with experimental binding assays on a limited number of antigenic variants to determine the epitopes to which antibodies bind.  Using both prospective and retrospective analyses, EpiScope was able to determine the epitopes in the majority of examples tested.  The second presentation, given by Mats Ohlin, Ph.D. and Professor, Department of Immunotechnology & SciLifeLab at Lund University, will demonstrate how antibodies from different germlines may evolve through divergent pathways based on preferred evolution patterns.  Kevin Hollevoet, Ph.D., Group Leader and Postdoctoral Fellow, Therapeutic and Diagnostic Antibodies, University of Leuven, Belgium, will describe the highly innovative and forward-thinking use of gene therapy approaches for the delivery of antibodies.  This is a new area that is now being pursued by several groups and offers novel approaches to solving antibody delivery issues, especially in cases where multiple antibodies or chronic high dosing schedules are required.  Karthik Viswanathan, Ph.D., Director of Research at Visterra, Inc., then will show how the use of a novel approach to modulating the interaction of IgGs with FcRn can result in increasing half-life while retaining robust structural stability and Fc receptor interactions.  Natalie Castellana, Ph.D., Chief Executive Officer of Digital Proteomics LLC, will show how a proteogenomic approach using deep sequencing and mass spectrometry can yield a unique picture of the serum immune repertoire.  Finally, William R. (Bill) Strohl will give an overview of current technologies being used in clinical stage antibodies and will tie those data together with highlights of the meeting to present a picture of the current and future state of innovative antibody therapeutics.

Interested in attending the meeting? Society members can save 15% on the registration fee! Contact us at membership@antibodysociety.org for the code.
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Membership is free for students and employees of the Society’s corporate sponsors.

Novel therapeutic indications for antibodies

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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! 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 novel therapeutic indications for antibodies, which will be held on Thursday December 14, 2017.

Intense efforts are underway in both academic and industrial labs to identify novel therapeutic targets using antibody technology. Much progress has been made, with many therapeutic antibodies populating the preclinical pipeline.  Promising therapeutic antibody targets will be presented in this session. First, John Cambier (University of Colorado Medical Center) will describe therapeutic antibodies that silence B cells by emulating peripheral immune tolerance.  Targeting CD20 by rituximab and similar cell-targeted therapies whose effects are mediated by B cell depletion has proven efficacious in a variety of autoimmune settings, but this approach has substantial risks due to long-term compromise of adaptive immunity. Dr. Cambier’s lab has pioneered an alternative, non-B cell depleting approach, which employs emasculated antibodies directed against antigen receptor components to induce a reversible state of anergy. This approach has proven effective in treatment of mouse models of type 1 diabetes, lupus and rheumatoid arthritis.

Uncontrolled fibrosis contributes to the pathogenesis of disease affecting many tissues, among these congestive heart failure, chronic kidney disease and cirrhosis. Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease with rapid, progressive loss of pulmonary function. TGF-β can induce fibroblast differentiation and is fundamental to the pathogenesis of pulmonary fibrosis. Protein tyrosine phosphatase α (PTP-α) has been shown to be a key regulator of the TGF-β-mediated fibrotic process in animal models of IPF.  Bo Yu (Larix Bioscience) will describe development of an inhibitory PTPα antibody for fibrotic diseases.

Despite aggressive LDL cholesterol reduction, substantial residual risk of coronary heart disease remains. APOC3 is a highly genetically validated therapeutic target for hypertriglyceridemia and cardiovascular disease. Daniel Rader (Perelman School of Medicine, University of Pennsylvania) will describe a series of anti-APOC3 monoclonal antibodies that markedly reduce triglycerides in a humanized mouse model. Targeting APOC3 with an antibody may be the next-generation therapy to reduce triglycerides and risk of coronary artery disease.

Another approach to reverse acute type 1 diabetes (T1D) with an anti-TLR4/MD-2 monoclonal antibody will be described by William Ridgway (University of Cincinnati College of Medicine).  New onset T1D (hyperglycemia, polyuria and weight loss) in nonobese diabetic (NOD) mice was attenuated by treatment with antagonistic TLR4/MD-2 specific monoclonal antibody (“TLR4-Ab”). 90% of NOD mice treated with TLR4-Ab showed a clinical response (delay in progression to end stage T1D), and 70% have permanent reversal of T1D. Successfully treated mice demonstrate decreased islet inflammation and preserved insulin staining of islet beta cells. Although TLR4-Ab does not stimulate T cells directly, immune tolerance can be restored to the adaptive immune system by this treatment. The TLR4/MD-2 pathway is a promising new therapeutic approach for treating autoimmunity.

FGF21 analogs belong to an emerging class of therapeutic candidates for type 2 diabetes and fatty liver disease. An engineered bispecific anti-FGFR1/β-Klotho agonist antibody that acts as a long-acting FGF21-mimetic will be described by Junichiro Sonoda (Genentech, Inc.). In addition, the mechanism of antibody action, together with the results from the first-in-human study performed with obese human subjects will be presented.

Preclinical studies showed the feasibility of targeting mural cell survival by using modulating antibodies capable of activating Notch 3 signaling. Joseph F. Arboleda-Velasquez (Harvard Medical School, Massachusetts Eye and Ear) will discuss implications of this work for prevalent causes of mural cell degeneration, including diabetic retinopathy and cerebral small vessel disease.

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.

Overcoming antibody delivery challenges

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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.

On Tuesday December 12, Paul J. Carter, Ph.D., Senior Director and Staff Scientist, Department of Antibody Engineering, Genentech, Inc., and Andreas Plückthun, Ph.D., Professor, Department of Biochemistry, University of Zürich, Switzerland will co-chair a session on overcoming antibody delivery challenges including brain and intracellular targets.

Antibody drug development is now a mature field with >60 marketed antibody therapeutics and hundreds more in clinical trials. Indeed, many of the more tractable and better understood targets for the treatment of human diseases have been extensively exploited for antibody drug development. This begs the question, where will new targets for future antibody drugs come from? One possible source of new targets for antibodies is in overcoming major delivery challenges that make some potential therapeutic targets challenging, if not impossible, to reach with conventional approaches. Presentations in this session will focus on three such delivery challenges highlighting basic research trying to understand the problems and translational studies attempting to overcome them.

The first delivery obstacle is to facilitate protein transport across the so-called blood-brain barrier (BBB) that prevents free diffusion of macromolecules from the blood into the interstitial fluid of the brain. This is an urgent and important problem to solve, given the tens of millions of individuals worldwide who are afflicted with neurodegenerative diseases and the lack of disease-modifying therapies. Incurable forms of brain cancer also represent another major unmet medical need. The second delivery challenge is increasing the efficiency of delivery of protein drugs to the lung. Addressing this challenge may facilitate the treatment of a range of serious lung diseases including autoimmunity, inflammation and cancers. The third delivery challenge is the “holy grail” for protein therapeutics of enabling proteins to cross the plasma membrane for delivery in a functional form to the cytosol. More than half of the targets for current drugs are located inside cells and accessible only to small molecule drugs. Efficient targeted delivery of protein drugs to access intracellular targets may greatly expand therapeutic target space. For example, blocking of protein-protein interactions is often readily possible with proteins and usually much more difficult with small molecules.

In the opening talk of this session, Jasi Atwal (Genentech) will present on bispecific antibodies to increase antibody delivery across the BBB into the brain. One arm of the bispecific binds to a receptor enriched at the BBB, such as transferrin receptor or CD98 heavy chain. The other arm of the bispecific binds to the brain target of interest. M. Jack Borrok (MedImmune) will describe targeting of caveolae-associated proteins to improve the delivery and efficacy of therapeutics that act within the lungs. Concurrently unwanted interactions with non-target tissues can be reduced. An alternative approach to delivery of protein drugs to the lung is by inhalation. This local lung delivery may provide rapid onset of pharmacologic action, as well as reduced systemic exposure and lower dose. Diane Van Hoorick (Ablynx) will provide a case study on an inhalable anti-respiratory syncytial virus (RSV) nanobody, ALX-0171, that is currently undergoing clinical evaluation for infants with RSV infection.

The final three talks will all approach the formidable problem of protein delivery, across the plasma membrane into the cytosol of cells. Wouter Verdurmen (Radboud University Medical Center, Nijmegen, The Netherlands) and collaborators developed a biotin ligase assay to quantify the relative efficiencies of various transport systems. This assay has been used to optimize protein transport by bacterial toxins and objectively compare it to cell-penetrating peptides and super-charged proteins. Next, Ernst Wagner (Ludwig Maximilians University, Munich, Germany) will describe the identification of potent intracellular delivery carriers derived from chemical evolution processes. Briefly, sequence-defined carriers from automated solid phase-assisted synthesis combine natural and artificial amino acids are combined with other transport elements, providing receptor-targeting and endosomal release function. In the final presentation of the session, Thomas Marlovits (Institute of Molecular Biotechnology, Austria) will describe bacterial type III secretion systems. These syringe-like “injectisomes” are megadalton in size and transport bacterial toxins across membranes directly into a eukaroytic host cells. Investigation of the injectisome led to the design of substrates that can be translocated directly into eukaryotic cells.

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.