Novel Antibodies to the C2-set Domain of CD33 for Acute Myeloid Leukemia Immunotherapy
Acute myeloid leukemia (AML) is a blood cancer associated with worse outcomes than other leukemias in children and improved treatments are needed. Engineering the immune system to fight AML (i.e. immunotherapy) is promising and the best-studied immunotherapy drug for AML is gemtuzumab ozogamicin (GO). GO acts by binding CD33, a protein found on leukemia cells in most AML patients, and delivering a chemotherapy drug specifically to those cells. Though children with AML treated with GO benefitted on average, half of patients did not benefit, simultaneously proving that CD33-targeted immunotherapy can be effective but also improved. One explanation for the suboptimal efficacy of GO is that CD33 exists in several forms – the full-length form (CD33FL) is recognized by GO, whereas a short form of the protein (CD33dE2) is not. In children with high amounts of CD33dE2, GO was not beneficial.
Therefore, I hypothesize that immunotherapy drugs recognizing both CD33 forms (CD33dE2+FL-targeting drugs) can improve on current CD33-targeting immunotherapy by attacking more leukemia cells in more patients. In our lab, we have shown that CD33dE2+FL-targeted drugs can be generated. Here, I will test my hypothesis by generating additional CD33dE2+FL-targeted drugs that could be used in humans and then testing these drugs head-to-head against CD33FL-targeted drugs in both a cell culture system and in murine models with humanized immune systems. I believe that my studies can efficiently determine the value of CD33dE2+FL-targeting immunotherapy while producing drugs ready for trials in children with AML, for whom better immunotherapy is required.