Rational Antibody Design
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Monoclonal antibodies represent an important class of targeted therapies. At least twenty-one monoclonal antibodies are FDA-approved for the treatment of a variety of serious, long-tem conditions, such as cancer and autoimmune disease. Clinical successes are underlined by the fact that in 2009 biologics account for approximately $20 billion dollars in revenue and represent the fastest growing sector of the pharmaceutical market. Our concept is to utilize a novel strategy to rationally design and engineer antibody-based molecules that bind to defined functional sites on target antigens (markers) and elicit therapeutic responses. These agents would represent a new class of antibodies or antibody/ligand hybrid molecules and would have significant commercial potential.
Our initial efforts in rational antibody design focus on critical sites on antibody molecules known as CDRs. These CDRs are the protein sequences that dictate the antibody's specificity for a target. We are using novel proprietary and public protein structure prediction software to model the interactions between proteins that play a critical role in cancer and other diseases. Using computational protein design and docking software, we are then engineering 1) antibody/ligand hybrid molecules replacing the original antigen binding sites (CDRs) with critical contact loops of the ligand and 2) re-engineering the CDRs of preclinically and clinically-validated antibodies to refocus their specificity onto similar functional sites of related targets. We anticipate these techniques will also be useful for other relevant applications such as affinity enhancement. We expect that the novel antibody-based molecules we are developing will have clinical utility for modulating therapeutically desirable signaling events.
Figure 1. MIS signaling inhibition. MIS mimetics RAD-1-0002 and RAD-1-0003 blocked MIS induced signaling in a reporter gene assay suggesting that these hybrid molecules are engaging the MISIIR ligand-binding site.
Our proof of concept work is focused on two target antigen systems, the Müllerian Inhibiting Substance Type II Receptor (MISIIR) and the ErbB family of receptor tyrosine kinases, both of which are highly relevant to the treatment of a variety of oncologic indications. Both projects have yielded lead molecules that demonstrate our ability to generate novel antibodies. We will subsequently extend our unique protein design methods to additional targets both within and beyond the oncology setting. Figure 1 shows three hybrid antibody molecules that we designed and built onto an originally non-binding antibody framework that are capable of altering signaling by the Müllerian Inhibiting Substance (MIS) through MISIIR. To date, other approaches to generate antibodies (e.g., hybridomas and combinatorial phage display) have failed to yield antibodies capable of eliciting these effects. As MIS induced signaling through this receptor has been shown to trigger the death of ovarian cancer cells, these results suggest our approach is capable of generating clinically relevant antibodies.
The inventors are highly experienced in the development of therapeutic antibodies, signal transduction pathways and molecular modeling. Gregory Adams, Ph.D. Immunology, University of California, Davis, has over 25 years of experience in developing and validating antibodies for the treatment of cancer. Matthew Robinson, Ph.D. in Genetics, University of Rochester School of Medicine and Dentistry has over 19 years of experience in signal transduction with 8 years directly related to the design of antibodies to disrupt signaling in cancer. Roland Dunbrack, Ph.D. in Biophysics, Harvard University has over 20 years of experience in molecular modeling of proteins and protein/protein interactions.
For licensing information, contactInna Khartchenko, MS, MBA
Associate Director, Office of Corporate Alliances Fox Chase Cancer Center
610 Old York Road, Suite 400
Jenkintown, PA 19046