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Architecture
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Antibody-drug conjugates (ADCs) are an established therapeutic approach in oncology used to selectively deliver potent cytotoxins directly to tumor cells, with the goal of maximizing toxicity in tumor cells, while minimizing toxicity to healthy cells. The antibody component is designed to selectively bind to a distinct antigen preferentially expressed on tumor cells. Upon binding to the antigen, most ADC molecules are internalized by the cancer cell wherein the warhead is released, causing cell death. Our next-generation ADC platform was engineered to specifically address efficacy and toxicity issues associated with currently approved ADCs. For example, our ADC platform has several key innovations regarding the linker (ie, the chemical structure attaching the warhead to the antibody) and the warhead. Once our ADCs are internalized, our unique linker is specifically cleaved by an enzyme called legumain. Legumain activity is elevated in cancer versus healthy cells; thereby preferentially targeting release of the warhead in cancer cells. In addition, our ADC platform is the first to use a kinesin spindle protein (“KSP”) inhibitor (“KSPi”) as a warhead to kill rapidly dividing cells. In clinical trials, KSP inhibitors that were administered systemically were found to be very toxic to rapidly dividing normal cells, such as blood and gastrointestinal cells; as such, they had a narrow therapeutic window, between killing normal versus cancer cells. By attaching our KSPi to antibodies directed against proteins found on cancer cells (eg, CD123 and CXCR5), we increase the therapeutic window by selectively targeting tumor versus healthy cells. In addition, our KSPi is chemically designed to be impermeable to cell membranes. This innovation, referred to as the “Cell Trapper™,” increases the potency in cancer cells by trapping the warhead within the cancer cell. Once the cancer cell dies, the Cell Trapper prevents entry of the warhead into neighboring normal cells, thus reducing unwanted toxicity. We believe this combination of innovative technologies (ie, antibody target; legumain-cleavable linker; KSPi and its Cell Trapper) has the potential to significantly minimize the side effects and improve the therapeutic benefit of ADCs. Toxicity of ADCs to normal cells has been a major limitation, thus far, for the optimization of this therapeutic drug class. This platform, once validated, offers the potential for application with other tumor-specific therapeutic antibodies.
Our bioconjugation program also includes an innovative small molecule drug conjugate (SMDC) platform. Our lead bioconjugation molecule is VIP236 for advanced and metastatic solid tumors (eg, triple negative breast cancer, colorectal cancer, small cell lung cancer, ovarian cancer and renal cell carcinoma). The small molecule ligand delivers a new chemical entity (NCE) warhead into the tumor stroma. The small molecule is designed to target an undisclosed surface antigen highly expressed on cancer cells. Our SMDC effectively targets cancer cells (10-fold increase in tumor vs plasma) and has demonstrated preclinical proof-of-concept in several in vivo solid tumor models.
PTEFb is an intracellular protein composed of two subunits, CDK9 and Cyclin-T. CDK9 is a transcriptional kinase that plays a central role in one of the processes that cancer cells use to survive and thrive: increased expression of cancer-promoting genes (eg, MYC and MCL-1). Therapeutics directed at targeting CDK9 and the PTEFb complex have often been hindered by inhibition of alternative targets in the CDK family. These non-CDK9 targets diminish the therapeutic window of this drug class. Our lead product candidate, VIP152, is a potent and highly selective CDK9 inhibitor optimized for intermittent intravenous treatment, which (by decreasing activity of this kinase) disrupts PTEFb function. VIP152 has shown target modulation (reduction of MYC and MCL-1 mRNA) and preliminary signs of clinical activity in Phase 1, notably in patient populations with high unmet medical needs.