Project 463275

A tumor marker called GD2 is present almost exclusively on the surface of tumors, such as 80% of human melanoma. GD2 activates pathways that give tumors a growth advantage, and causes immunosuppression giving tumors the ability to evade the immune system, acting like an immune-inhibitor comparable to the well-known PDL-1 molecule. In spite of GD2 being an attractive therapeutic target, it remains underexploited because it is very difficult to generate antibodies against it. Indeed, after 50 years of basic research and 35 of clinical research there is only one anti-GD2 monoclonal antibody approved by FDA for therapy, but for a very rare form of cancer that has no other options. This is because the GD2 therapy provides very limited clinical benefits, and has a poor therapeutic index as it causes serious side effects. Better tools are needed to exploit GD2 as a therapeutic target. We made 11 unique monoclonal antibodies against GD2 (patented). Two of these mAbs (clone 6 and clone 19) are being developed for cancer diagnostics under a Commercialization program supported by CIHR, and will be submitted to FDA in August 2022. Other mAbs are under development for therapeutic uses, which is the goal of this grant. In preliminary data we show in mouse models of melanoma that 2 mAbs (8H3-clone 4 and 4A3-clone 17) as monotherapy afford a significant benefit and a high therapeutic index without the side effects of the FDA-approved mAb. Furthermore, 8H3-clone 4 (other mAbs were not evaluated yet) significantly potentiates the therapeutic index of anti-PD1 therapy. Our goal in this grant is to optimize the therapeutic efficacy of the anti-GD2 mAbs, as monotherapy and in combination with standard anti-PD1 treatments, enabling a reduced dose and a reduced frequency of treatment. This will result in a pre-clinical program that can be translated clinically, to deliver optimized treatments to patients, lower side effects, and lower costs to healthcare.