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.

Outcomes Following GD2-Directed Postconsolidation Therapy for Neuroblastoma After Cessation of Random Assignment on ANBL0032: A Report From the Children's Oncology Group

“…Development of next-generation anti-GD2 antibodies may help decrease treatment-associated pain. 24,25 The rate of HACA positivity in this cohort was similar to that reported in the randomized cohort. The development of HACA was associated with lower dinutuximab levels and decreased toxicity, as reported previously.…”

“…Development of next-generation anti-GD2 antibodies may help decrease treatment-associated pain. 24,25…”

Immunotherapy of Neuroblastoma: Facts and Hopes

“…However, despite potent in vitro destruction of tumor cells by these bifunctional and trifunctional agents, their potency in mice or patients bearing solid tumors has not yet matched their potency against leukemia; possibly implicating the immune-excluded/ immune-suppressive tumor microenvironment of many solid tumors, including neuroblastoma (20). Unique engineering strategies are also being deployed to reduce or avoid pain associated with anti-GD2 mAb, including use of alternative or mutated mAb isotypes to avoid paininducing complement activation (88,89), or mAb strategies that require corecognition of two separate tumor antigens that are coexpressed simultaneously on the same tumor cells, but not coexpressed on cells from normal tissues (90). In addition, refinement of the antigen-binding component of the Fab (or ScFv) of the antitumor antibody, can identify more advantageous binding kinetics to facilitate improved interactions with the tumor cell surface for any antibodybased therapeutic modality (mAbs, ADCs or CARs).…”