Optimizing CD33-Targeted Antibody-Drug Conjugate Therapy for Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a difficult-to-treat blood cancer, and many children with AML will eventually die from intensive chemotherapies and bone marrow transplantation. Antibodies against CD33, a protein found on the surface of AML cells of most patients, have been developed hoping to improve these outcomes. Indeed, gemtuzumab ozogamicin (GO), an antibody with a cell toxin attached (“antibody-drug conjugate” [ADC]) that binds to the distal, V-set portion of CD33, has benefitted some children with AML; however, many do not benefit despite having CD33 present on their AML cells. As one limitation, the amount of CD33 expressed on AML cells limits the efficacy of GO. In other words, there is not enough target (CD33) present for the ADC to bind and deliver an effective dose of the cell toxin to kill the AML cell. With the goal of developing novel CD33-targeted therapies, our laboratory has previously raised new antibodies that bind the proximal, C2-set portion of CD33 (i.e., are CD33C2-set antibodies). In my studies, I found that the antibody used in GO can bind simultaneously with CD33C2-set antibodies, thereby increasing the total amount of antibody bound to CD33 at any given time. Building on these findings, I now plan to study how CD33-targeted ADCs can be improved by dual targeting the C2-set and V-set domain of CD33. Anticipated data from the proposed studies will lay the groundwork for a new, better way to treat children with AML using CD33-targeted ADCs.
Project Goals
My project aims to overcome current limitations of GO by developing a strategy that targets the CD33 protein on leukemia cells with 2 antibodies at the same time. By doubling the number of antibody molecules capable of binding CD33 simultaneously (by binding the V-set with one antibody and the C2-set domain with another), my current data suggest that this will lead to an increased intracellular delivery of toxic payload drugs, eventually increasing the chance of AML cell death. I will test this hypothesis in two different, but complementary, ways. In the first, I will make a new ADC that targets the C2-set domain (CD33C2-set ADC) to be used in combination with GO. In the second, I will make a new “biparatopic” ADC (bpADC) that is able to bind both the CD33 V-set and C2 set domains simultaneously. With these new tools in hand, I will then conduct experiments in human AML cell lines and primary AML patient samples to evaluate if dual-targeting CD33 ADC strategies are better than what is possible with GO alone. While this is a novel approach in AML, similar dual-targeting strategies have had success in other solid and hematologic cancers. Ultimately, I hope that the results of these studies will provide critical insights on how to best target CD33, with the goal of driving the development of new, more effective CD33-targeted therapies for children with AML and other CD33-positive cancers.
