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7:45 am Continental Breakfast in the Exhibit Hall
8:30 Chairperson’s Opening Remarks
Gerald Casperson, Ph.D., Associate Research Fellow, Biotherapeutics, Pfizer Global Research & Development
8:35 Trastuzumab Conjugate for the Treatment of Trastuzumab-Resistant Human Breast Cancer: Increasing Magnitude and Duration of Response
Wen Jin Wu, Ph.D., Principal Investigator, Division of Monoclonal Antibodies, OBP/OPS/CDER, Food and Drug Administration
Our laboratory in the Division of Monoclonal Antibodies at FDA has investigated the mechanisms underlying trastuzumab-resistance and is pursuing new ways to increase the magnitude and duration of the response to the trastuzumab treatment. Using a Rac1 specific inhibitor, NSC23766, to treat trastuzumab-resistant cells, we found that trastuzumab-resistant cells became sensitive to the trastuzumab treatment. We plan to develop a new molecular entity (NME), whereby trastuzumab will be covalently conjugated with NSC23766.
9:05 Fc-Optimized Monoclonal Antibody for HER2- Expressing Tumors
Jeffrey L. Nordstrom, Ph.D., Director, Product Development Research, MacroGenics, Inc.
We have developed an anti-HER2 mAb with an Fc engineered for increased binding to both alleles of the CD16A activating Fc receptor and decreased binding to the inhibitory receptor, CD32B. The optimized Fc enhances ADCC activity against low-expressing HER2+ tumor lines and enhanced antitumor activity against HER2+ xenografts in mice transgenic for the low-binding allele of human CD16A. Breast cancer patients carrying the low-binding allele have reduced clinical responses to trastuzumab; the Fc-optimized anti-HER2 mAb could potentially benefit these patients.
9:35 Optimization of a Monoclonal Antibody for Improved Anti-Tumor Efficacy
Gerald Casperson, Ph.D., Associate Research Fellow, Biotherapeutics, Pfizer Global Research & Development
We will describe the optimization of an antibody which has recently entered the clinic for Oncology indications. We engineered this antibody to greatly enhance its efficacy and to minimize the likelihood of immunogenicity. We plan to disclose the target and will describe the process and technology used for optimization including data from both in vitro and in vivo pharmacology.
10:05 Coffee Break, Poster and Exhibit Viewing
11:05 Recombinant Immunotoxins for the Treatment of Hematologic Malignancies
Robert J. Kreitman, Ph.D., Principal Investigator, Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health
Recombinant immunotoxins, containing a fragment of a monoclonal antibody (Mab) genetically fused to a protein toxin, kill cells by binding to the cell, internalizing, and transporting a toxin fragment to the cytoplasm where it catalytically inhibits protein synthesis, stimulating apoptosis. Unlike naked MAbs, they do not require ADCC or CDC, and unlike radioimmunotherapy, they do cause bystander damage to normal marrow cells. Recombinant immunotoxins with clinical activity, particularly in hairy cell leukemia, include LMB-2, targeting CD25, and BL22 and its improved version HA22 (CAT-8015), targeting CD22.
11:35 Engineered Avibodies Optimized for Clinical Diagnosis and Therapy
Peter Hudson, Ph.D., CSO, Avipep Laboratories, Avipep Pty, Ltd.
Avibodies are scFvs that self-associate into multivalent dimers or trimers and provide unique and superior properties to enhance therapeutic payloads (radionuclides, toxins, drugs etc). We have evaluated several oncology applications and have optimized tumor-to-blood ratios for imaging and therapy whilst reducing undesired renal accumulation. Increasing the apparent molecular weight by PEG derivatization plus radio-labeling provides high xenograft tumor uptake (over 50% ID/gm) and with a biodistribution profile optimal for therapy or in vivo imaging.
12:05 Luncheon Presentations (Sponsorship Opportunities Available) or Lunch on Your Own
1:05 Break
1:25 Chairperson’s Remarks
Ira Pastan, Ph.D., Head, Molecular Biology Section, NCI, NIH
1:30 Antibody Therapeutics: Isotype and Glycoform Selection
Roy Jefferis, Ph.D., Professor of Molecular Immunology University of Birmingham, Division of Immunity & Infection
Antibody therapeutics may be developed to achieve one, or more, of several outcomes: i) killing of cells or organisms, e.g. cancer cells, bacteria; ii) neutralization of soluble molecules, e.g. cytokines, toxins; iii) acting as agonists or antagonists of cellular receptors. Consequently the choice of antibody isotype is a critical decision; however, functional activity is also dependent on the IgG-Fc glycoform. Glycosylation and protein engineering may be employed to generate antibody formats and homogeneous IgG glycoforms considered optimal for given clinical indications.
2:00 Early Stage Engineering to Improve Pharmaceutical Properties of Antibodies
Alexey Lugovskoy, Ph.D., Head of Molecular Modeling and NMR, Drug Discovery, Biogen IDEC, Inc.
Unfavorable pharmaceutical properties of antibodies can limit their potential as drugs. To mitigate this risk we apply structure-guided engineering approaches in early antibody discovery programs. We will present examples where stability and solubility of antibodies were improved and discuss the incorporation of these technologies in cycle one design.
2:30 Networking Refreshment Break
3:00 Deimmunizing Non-Human Proteins
Ira Pastan, Ph.D., Head, Molecular Biology Section, NCI, NIH
Many non-human proteins have useful therapeutic properties, but their use is limited because of their immunogenicity. We have shown immunotoxins which contain portions of Pseudomonas exotoxin A have therapeutic benefit in leukemias where the immune system is suppressed. To make immunotoxins useful in patients with normal immune systems, we have mapped and removed by mutation all 7 major B cell epitopes. The new immunotoxin (HA22-LR-8X) has full cytotoxic activity and anti-tumor activity yet has very low immunogenicity in mice. Our approach should be useful to deimmunize other foreign proteins.
3:30 Antibody Optimization from Pharmacokinetic-Pharmacodynamic Perspectives
Liang Zhao, Ph.D., Clinical Pharmacology Reviewer, FDA/CDER/OTS/OCP
PK-PD provides critical quantitative measures for antibody drug candidates, not only at the discovery stage, but also at late phases of development cycle. It integrates any knowledge available of drugs in the same category, dosing needs for therapeutic effect, mechanism of action, disease progression, shared characteristics of antibody drugs, and clinical outcomes. Overview from all these perspectives will greatly benefit new antibody drug design from scratch
4:00 Probodies: Site-Directed Antibodies to Improve Therapeutic Indices
Nancy Stagliano, Ph.D., CEO, CytomX Therapeutics, LLC
Although antibodies are highly specific for their target, the target itself is often not confined to diseased tissues. Mechanism-based activities of antibodies cause side effects, the need for dose delay and reduction and potentially reduced therapeutic benefit. In addition, their high potency allows for fewer targets that can be safely and effectively drugged. Protease-activated antibodies, Probodies, are a new, discovery-stage therapeutic with the potential for dramatically improved therapeutic indices. In the circulation, Probodies exist in a masked or inactive state. In contrast, endogenous proteases within diseased tissues activate Probodies locally and produce the desired therapeutic effect. Using our proprietary approach to engineering therapeutic antibodies, we will describe our early stage oncology programs including Probodies to EGFR and a cancer stem cell target, including preclinical in vivo data.
4:30 End of Conference
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