Pharmacokinetic / Pharmacodynamic Optimization of ADC Therapy for Acute Myeloid Leukemia

点击翻译按钮获取中文摘要

This project utilizes mechanistic pharmacokinetic / pharmacodynamic modeling to guide the development of new therapeutic strategies, and new therapeutic agents, to improve the safety and efficacy of antibody-drug conjugate (ADC) therapy for acute myeloid leukemia (AML). The project will generate new monoclonal antibodies and nanobodies with specificity for three surface proteins overexpressed in AML (CD123, CLL1, TIM3). The new antibodies and nanobodies will be used as targeting vectors to deliver candidate payload molecules (MMAE, DM4, SN38, Dxd) to AML cells (Aim #1). Within experiments proposed in Aim #2, the targeting vectors will be assembled into bispecific constructs to test the hypothesis that bispecific ADCs enable improved efficacy and decreased off-site on-target toxicity. Aim #3 will investigate a newly developed inverse targeting strategy, where co-treatment with payload binding antibody fragments (i.e., Payload Binding Selectivity Enhancers, PBSE) is employed to decrease the delivery of payload molecules to healthy tissues, enabling reduced off-site off-target toxicity. PBSE with high affinity for MMAE, DM4, SN38, and Dxd will be evaluated for utility in preventing the off- site, off-target toxicity that results from the exposure of healthy cells to released (i.e., “free”) payload. Due to the selective binding of PBSE to free payload, with little or no binding of PBSE to intact ADCs, we hypothesize that our new PBSE agents will allow decreased toxicity of anti-AML ADC therapy, without negatively impacting ADC efficacy. Aim #4 will perform in vivo experiments in mouse models of human AML to evaluate the effects and toxicities of monospecific anti-AML ADCs and bispecific ADCs, with or without cotreatment with PBSE. Due to our development of several targeting vectors, each with a wide range of possible characteristics (e.g., affinity, modality [nanobody, mAb], bispecificity), and due to our intent to consider several payload molecules, with or without PBSE co-treatment, many permutations may be considered. Additionally, complete and appropriate experimental evaluation of relationships between ADC attributes and therapeutic utility is not possible in animal models, due to the unavailability of models with appropriate co-expression patterns of human antigens on healthy cells, AML bulk cells, leukemic blasts, and leukemic stem cells. To address these complexities and limitations, mechanistic PKPD modeling and simulation will be employed throughout the project to predict effects and toxicities in mouse models and in AML patients, to facilitate engineering efforts (e.g., predicting relationships between affinity of bispecific binding arms and therapeutic selectivity), and to guide selection of constructs for in vivo evaluations.