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Rationally Designed Anti-Mullerian Inhibiting Substance Type II Receptor Antibodies

Ref. No. 276-GA
 

Background

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-term 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.

Summary Invention

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 preclinically 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. Figure 1 shows three hybrid antibody molecules that were 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 the approach is capable of generating clinically relevant antibodies.

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. 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. Figure 1 shows three hybrid antibody molecules that were 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 the approach is capable of generating clinically relevant antibodies

Patent Status:

US Patent # US 9,611,321 B2 issued April 4, 2017

For Licensing/Partnering information, please contact:

Inna Khartchenko, MS, MBA
Director, Technology Transfer
Tel.: 215-214-3989
E-mail: inna.khartchenko@fccc.edu

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