Nai-Kong V. Cheung: Overview
Monoclonal antibodies (mAb) destroy tumor cells by inducing cell death, complement-mediated cytotoxicity, and antibody-dependent cellular cytotoxicity (ADCC). With first generation mouse antibodies, metastatic neuroblastoma in bone marrow and bones, brain and leptomeninges can now be controlled with antibodies 3F8 and 8H9 (Omburtamab), both developed at MSK. Our next generation mAbs are chimeric/humanized antibodies (e.g. hu3F8 or Naxitamab) and their bispecific forms selective for targets on solid tumors (GD2, GPA33, L1CAM, and HER2) and leukemia/lymphoma (CD19, CD22, CD33), as well as T-cell epitopes (WT1, LMP2). Protein engineering has produced unique antibody platforms with improved pharmacokinetics, therapeutic index and curative potential. T cells can now be driven by bispecific antibodies (BsAb) deep inside human solid tumors, turning “cold” environment into “inflamed” stroma, preparing tumor for ablation. The addition of immune checkpoint inhibitors can also greatly enhance these anti-tumor effects. Furthermore, radioisotopes can be delivered using BsAb in pretargeting strategies to achieve therapeutic ratios (>75:1) not achievable with conventional methods (5:1). At these ratios, neuroblastoma, colon cancer and breast cancer can be ablated with no histological or clinical toxicities in preclinical models. Using novel cages to contain these isotopes, different radioactive particles (gamma, positron, beta or alpha) can be selectively delivered to tumors for both diagnosis and therapy (theranostics). These novel antibodies are being produced under an accelerated drug development program in the Department of Pediatrics at MSK for clinical applications for both pediatric and adult cancers.
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