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Rationally Designed Anti-Mullerian Inhibiting Substance Type II Receptor Antibodies
Monoclonal antibodies represent an important class of targeted therapies. Up to date, at least sixty monoclonal antibodies are FDA-approved for the treatment of a variety of serious, long-term conditions, such as cancer, cardiovascular, respiratory, hematology, autoimmune diseases, and infections. Clinical successes are underlined by the fact that biologics represent the fastest growing sector of the pharmaceutical market. The Global monoclonal antibodies market is estimated to reach 218.97 Billion USD by 2023 with a CAGR of 12.5 % during the period 2017-2023.
Researchers from Fox Chase Cancer Center developed 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.
The 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. Novel proprietary and public protein structure prediction software was used to model the interactions between proteins that play a critical role in cancer and other diseases. Computational protein design and docking software were used for 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 pre-clinically and clinically-validated antibodies to refocus their specificity onto similar functional sites of related targets. These techniques will also be useful for other relevant applications such as affinity enhancement and the novel antibody-based molecules will have clinical utility for modulating therapeutically desirable signaling events.
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 the ability to generate novel antibodies. 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 the approach is capable of generating clinically relevant antibodies.
Patent issued US 8,883,978 (2017).
For Licensing/Partnering information, please contact:
Inna Khartchenko, MS, MBA
Director, Technology Transfer