Pharmacokinetic / Pharmacodynamic Optimization of ADC Therapy for Acute Myeloid Leukemia

该项目利用机制药代动力学/药效学模型来指导新药物的开发。 治疗策略和新的治疗剂，以提高抗体-药物缀合物的安全性和功效 (ADC)急性髓细胞白血病（AML）的治疗。该项目将产生新的单克隆抗体， 纳米抗体对AML中过表达的三种表面蛋白（CD 123、CLL 1、TIM 3）具有特异性。新 抗体和纳米抗体将用作靶向载体以递送候选有效负载分子（MMAE， DM 4、SN 38、Dxd）至AML细胞（目标#1）。在目标#2中提出的实验中，靶向载体将是 组装成双特异性构建体以检验双特异性ADC能够改善功效和 降低了非现场靶向毒性。目标#3将研究一种新开发的反向瞄准策略，其中 与有效负载结合抗体片段共处理（即，有效载荷结合选择性增强剂，PBSE）是 用于减少有效载荷分子向健康组织的递送，使得能够减少非位点脱靶 毒性将评价对MMAE、DM 4、SN 38和Dxd具有高亲和力的PBSE在预防脱- 位点，由健康细胞暴露于释放的（即，“自由”）有效载荷。由于 PBSE与游离有效载荷的选择性结合，而PBSE与完整ADC的结合很少或没有，我们假设 我们的新PBSE药物将降低抗AML ADC治疗的毒性，而不会对ADC产生负面影响。 功效目的#4将在人AML的小鼠模型中进行体内实验，以评估其作用和 在有或没有与PBSE共治疗的情况下，单特异性抗AML ADC和双特异性ADC的毒性。由于 我们开发了几种靶向载体，每种载体都具有广泛的可能特征（例如，亲和力， 形式[纳米抗体，mAb]，双特异性），并且由于我们打算考虑几种有效载荷分子， 在没有PBSE共同治疗的情况下，可以考虑许多排列。此外，完整和适当 无法在动物中进行ADC属性与治疗效用之间关系的实验评价 模型，由于在健康受试者中不存在具有适当的人抗原共表达模式的模型， 细胞、AML散装细胞、白血病母细胞和白血病干细胞。为了解决这些复杂性和局限性， 在整个项目中，将采用PKPD机制建模和模拟来预测效果， 小鼠模型和AML患者中的毒性，以促进工程努力（例如，预测关系 在双特异性结合臂的亲和力和治疗选择性之间），并指导用于在 体内评价。

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.