治疗抗体之临床开发

4月28日 (一)

PRECLINICAL DEVELOPMENT

2:00 Chairperson's Opening Remarks
Mohammad Tabrizi, Ph.D., Director, MedImmune

2:05 Normalizing Tumor Vessels and Microenvironment to Treat Cancer: From the Bench to Bedside and Back
Rakesh K. Jain, Ph.D., Andrew Werk Cook Professor of Tumor Biology, Director, Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School
Solid tumors require blood vessels for growth, and many new cancer therapies are targeted against the tumor vasculature. The widely held view is that these antian-giogenic therapies destroy the tumor vasculature, thereby depriving the tumor of oxygen and nutrients. Indeed that is the ultimate goal of antiangiogenic therapies. However, emerging preclinical and clinical evidence support an alternative hypothesis – that judicious application of agents that block angiogenesis directly (e.g., Avastin, Recentin) and indirectly (e.g., Herceptin) can also transiently “normalize” the abnormal structure and function of tumor vasculature. In addition to being more efficient for oxygen and drug delivery, the normalized vessels are fortified with pericytes, which can hinder intravasation of cancer cells – a necessary step in hema-togenous metastasis. Drugs that induce vascular normalization can also normalize the tumor microenvironment – reduce hypoxia and interstitial fluid pressure – and thus increase the efficacy of many conventional therapies if both are carefully scheduled. Reduced interstitial fluid pressure can decrease tumor-associated edema as well as the probability of lymphatic dissemination. Independent of these effects, alleviation of hypoxia can decrease the selection pressure for a more malignant phenotype. Finally, the increase in proliferation of cancer cells during the “vascular normalization window” can potentially sensitize tumors to cytotoxic agents. Our recent Phase II clinical trials in patients with rectal carcinomas and glioblastomas (GBM) support our pre-clinical findings on vascular normalization. Moreover, in GBM patients, the normalization window – identified using advanced MRI techniques – can last one to four months, and the resulting changes in tumor vasculature correlate with circulating molecular and cellular biomarkers in these patients. The encouraging results on patients survival from the GBM Phase II trial has led to an international multi-center randomized Phase III clinical trial in GBM patients and has spawned a number of trials for non-CNS tumors.

2:35 Technologies for the Discovery of Therapeutic Monoclonal Antibodies
Larry L. Green, Ph.D., Consultant, Green Consulting
Monoclonal antibodies are now well-validated human therapeutics. While new technologies hold great promise for enhancing the utility and safety of monoclonal anti-bodies and their related molecules, the initial work of designing and then discovering good therapeutic leads is still a major challenge. This talk will give an overview of the benefits of the platform technologies for generation of monoclonal antibodies and antibody-like molecules and then review new and re-vitalized technologies for improving utility and safety.

3:05 Refreshment Break in the Exhibit Hall

3:45 Optimizing Engagement of the Immune System by Anti-Tumor Antibodies: An Engineer's Perspective
John R. Desjarlas, Ph.D., Vice President, Research, Xencor, Inc.
A unique property of monoclonal antibodies, and a principal reason for their success of cancer therapeutics, is their ability to engage the immune system. A growing set of data supporting the relevance of Fc-mediated effector functions to anti-tumor efficacy has motivated efforts to enhance the interactions between antibodies and Fc receptors expressed on immune cells. Although current approaches have considerable promise for improved clinical performance, the immunobiology of tumors, antibodies, and Fc receptors continues to evolve. This presentation will review what is known and what is not known about the interactions between therapeutic antibodies and the immune system, with the goal being progress toward clear target profiles for effector engineering efforts.

4:15 Challenges in Development of Monoclonal Antibodies
Steve Coats, Ph.D., Director of Oncology Research, MedImmune
One of the unique challenges facing antibody based preclinical development in oncology is the reactivity of the antibody to relevant target antigens in preclinical efficacy and safety models. This presentation will focus on the advantages and disadvantages of different in vitro and in vivo model systems for screening anti-bodies for potency and in vivo efficacy. In addition, data will be presented using both transgenic animals as well as surrogate antibodies to test antibodies that lack murine cross-reactivity against the target antigen. Lastly, the utility of these model systems to understand the mechanism of action as well as pharmacodynamic readouts will be discussed.

4:45 Development of a New Fully Human Anti-CD20 Monoclonal Antibody for the Treatment of B-Cell Malignancies
Gadi Bornstein Ph.D., Principle Scientist, AstraZeneca R&D
In spite of the widespread use of Rituximab, a chimeric monoclonal antibody with demonstrated efficacy in the treatment of non-Hodgkin's lymphomas, there is a recognized need to develop fully human antibodies with improved efficacy. Towards this end, using XenoMouse technology, a fully human IgG1 monoclonal anti-body specific to human CD20 was generated. This antibody, denoted mAb 1.5.3, evoked enhanced pro-apoptotic activity in vitro, as compared to Rituximab, in the Ramos human lymphoma cell line, and elicited improved antibody-dependent cellular cytotoxicity (ADCC) in human B-lymphoma cell lines. To recapitulate various aspects of acquired resistance to Rituximab, as observed in a subpopulation of patients, Rituximab-resistant clones were established from lymphoma lines; interestingly, mAb 1.5.3 demonstrated superior cytolytic activity in vitro against engineered Rituximab-refractory lymphoma clones, as well as across multiple human B-lymphoma and chronic B-cell leukemia lines. Furthermore, mAb 1.5.3 exhibited enhanced anti-tumor activity in Rituximab-sensitive cell lines and refractory engineered lymphoma clones in vivo. Lastly, mAb 1.5.3 produced a superior B-cell depletion profile in lymph node organs and bone marrow as compared to Rituximab in a primate PD model. In summary, these results demonstrate the superior anti-tumor activity of mAb 1.5.3 relative to Rituximab and its potential for improved clinical activity in the treatment of B-cell malignancies.

5:15-6:45 pm Networking Cocktail Reception in the Exhibit Hall