Pan-Cancer Reactive NDC80 CAR

SK2021-083
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SUMMARY OF INVENTION

The lack of known cancer-specific cell surface proteins has limited the development of new CAR T-cell therapeutics. Moreover, targets are often limited to a single cancer subtype which restricts the number of patients that could benefit from this modality. To identify a CAR T-cell target with broad expression across both hematologic and nonhematologic cancers, MSK investigators performed computational analyses on HLA-A*02:01 presented peptides from multiple cancer cell lines. Analysis of shared biological functions between the cell lines identified an abundantly presented NDC80 peptide. NDC80 has previously shown to be: 1) implicated in aneuploidy and tumorigenesis, 2) highly expressed across several tumors, and 3) correlated with tumor grade and prognosis, making it a desirable oncology target.

To address this target, investigators collaborated with Eureka Therapeutics to develop an NDC80 TCR-mimic CAR (NDC80 CAR). During this process, NDC80 CARs were characterized until a lead candidate was selected that killed all cancer cell lines in both a dose-dependent and target-specific manner. The lead candidate was then evaluated in vivo in leukemia and mesothelioma tumor models and benchmarked to MUC16-targeting CAR-T cells. In both models, the lead NDC80 CAR led to profound improvements over the MUC16 control, with 100% of rodents alive at 60-days compared to 0% of the MUC16 control in the mesothelioma model. The lead optimized NDC80 CAR is available for license  and could enable a therapeutic approach to target multiple cancer subtypes.

ADVANTAGES

NDC80 is highly expressed across hematologic and non-hematologic cancers and enables targeting of:

  • Oncogene expressing cancer cells- overexpression of NDC80 shown to be associated with tumor formation in an inducible rodent model (Diaz-Rodríguez et al., 2008).
    • Limits potential for tumor escape by downregulation of NDC80.
  • Multiple cancer types- NDC80 peptide was detected in >90% of A*02+ cancer cell lines.
    • Mass spectrometry analysis of cancer cell lines suggests that the NDC80 CAR may be active against both hematologic (ex: AML, B-ALL, multiple myeloma, DLBCL) and nonhematologic (ex: melanoma, breast cancer, colon cancer, prostate cancer, mesothelioma) cancers.

MARKET OPPORTUNITIES

The NDC80 CAR is designed to be effective against multiple liquid and solid tumors. The CAR recognizes NDC80 peptide presented by HLA-A*02:01 which is among the most frequently presented HLA alleles in the US (~40% of the population; Pearlman et al., 2021). The NDC80 peptide has also been found on other A*02 suballeles (ex: A*02:02, :03, :04, :07, :11) which could expand the total addressable market.

PUBLICATION

Klatt et al., A TCR mimic CAR T cell specific for NDC80 is broadly reactive with solid tumors and hematologic malignancies. Blood. 2022 (link)

STAGE OF DEVELOPMENT

Preclinical

PATENT INFORMATION

PCT application (PCT/US2021/054123) was filed in October 2021

LEAD INVESTIGATOR

David A. Scheinberg, MD, PhD, Chairman, Experimental Therapeutics Center; Vincent Astor Chair; Deputy Director, SKI, for Therapeutic Discovery

CONTACT INFORMATION

James Delorme, PhD

Licensing Manager
E-mail: [email protected]
 

Stage of Development

Animal studies

Indications