Improving Specific Targeting of Tumors Through Bispecific SNIPER Antibodies

Abstract

GD2 is expressed on neuroblastomas, as well as melanomas, small cell lung cancers and sarcomas. Anti-GD2 mAb can be used to treat these cancers and is part of the standard care for neuroblastoma. Expressed minimally on normal tissues, GD2 is expressed on some nerve cells. Thus, anti-GD2 treatment can cause neuropathic pain. To increase tumor specificity, we developed a bispecific SNIPER antibody, INV721, to simultaneously target 2 tumor antigens. One arm of INV721 is specific to GD2 and the other arm is specific to B7H3. B7H3 is overexpressed on multiple tumor types, including those listed above, with minimal expression on most normal cells (some expression on liver cells), and absent on nerve cells. The Fab arms targeting GD2 and B7H3 are each low-moderate affinity, such that INV721 will only bind with high affinity when both arms of INV721 bind to their antigens on the same cell. This high-affinity binding requires expression of both GD2 and B7H3, resulting in high-specificity of the SNIPER to tumor cells. To test the in vivo binding affinity of our bispecific antibody, INV721 was radiolabeled with ⁸⁹Zr. Mice bearing GD2/B7H3-expressing tumors were intravenously injected with ⁸⁹Zr-labeled INV721 and its longitudinal in vivo biodistribution was monitored via positron emission tomography imaging. ⁸⁹Zr-INV721- showed elevated and persistent accumulation in the tumor with minimal uptake in normal tissues. ⁸⁹Zr-radiolabeled isotype control antibody displayed significantly lower tumor uptake demonstrating the specificity of INV721. The goal of this SNIPER-antibody is to enhance the tumor-specific delivery of therapeutic mAbs, which may decrease toxicity and improve efficacy for cancers expressing both GD2 and B7H3.