Pharmacokinetic / Pharmacodynamic Optimization of ADC Therapy for Acute Myeloid Leukemia

急性髓系白血病 ADC 治疗的药代动力学/药效学优化

基本信息

批准号：
10561230
负责人：
Joseph P Balthasar
金额：
$ 42.69万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10561230
关键词：
Acute Myelocytic Leukemia Address Affinity Animal Model Antibodies Antibody-drug conjugates Antigens Binding Biological Assay Bispecific Antibodies Blast Cell Cell Culture Techniques Cell membrane Cells Characteristics Development Dose Drug Delivery Systems Drug Kinetics Drug toxicity Engineering Enhancers Evaluation Extracellular Domain Future Human IL3RA gene Immunoglobulin Fragments Investigational Drugs Life Membrane Proteins Modality Modeling Monoclonal Antibodies Mus New Agents Patients Pattern Pharmaceutical Preparations Pharmacodynamics Pharmacology and Toxicology Plasma Process Safety Site Specificity Surface Antigens Testing Therapeutic Therapeutic Agents Tissues Toxic effect Validation Work acute myeloid leukemia cell arm cancer cell chemical conjugate cytotoxic cytotoxicity design effective therapy experimental study human model improved in vivo in vivo evaluation leukemia leukemic stem cell mathematical model models and simulation mouse model nanobodies novel therapeutic intervention novel therapeutics off-target site overexpression patient population pharmacodynamic model pre-clinical predictive modeling prevent research clinical testing safety testing targeted agent treatment strategy tumor vector

项目摘要

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.

该项目利用机械药代动力学 /药效学建模来指导新的治疗策略和新的治疗剂，以提高抗体 - 药物结合物的安全性和效率（ADC）急性髓样白血病（AML）的治疗。该项目将产生新的单克隆抗体和在AML中过表达的三种表面蛋白的特异性（CD123，CLL1，TIM3）。新的抗体和纳米体将用作靶向向量，以提供候选有效载荷分子（MMAE，MMAE， DM4，SN38，DXD）到AML细胞（AIM＃1）。在AIM＃2中提出的实验中，目标向量将是组装成双特异性结构，以测试双特异性ADC可提高效率和降低现场靶向毒性。 AIM＃3将调查新开发的反向定位策略，其中与有效载荷约束抗体片段（即有效载荷约束选择性增强器，PBSE）共同处理是用来减少有效载荷分子向健康组织的递送，从而使场外脱离目标减少毒性。将评估对MMAE，DM4，SN38和DXD高亲和力的PBSE 位置，脱靶毒性是由健康细胞暴露于释放（即“免费”）有效载荷的。由于 PBSE的选择性结合到免费有效载荷，而PBSE对完整ADC的结合很少或没有结合，我们假设我们的新PBSE代理将允许抗AML ADC疗法的毒性降低，而不会对ADC产生负面影响 AIM＃4将在人AML的小鼠模型中进行体内实验，以评估效果和单特异性抗AML ADC和双特异性ADC的毒性，有或不使用PBSE共进行。由于我们开发了几个靶向向量，每个载体具有广泛的特征（例如，亲和力，模态[纳米机，mab]，双特异性），由于我们打算考虑使用或使用多个有效载荷分子没有PBSE共同处理，可以考虑许多排列。此外，完整且适当在动物中无法实现ADC属性与治疗效用之间关系的实验评估由于模型没有适当的共表达模式的人类抗原对健康的模型细胞，AML散装细胞，白血病爆炸和白血病干细胞。为了解决这些复杂性和局限性，机械性PKPD建模和模拟将在整个项目中进行，以预测效果和小鼠模型和AML患者中的战术性，以促进工程工作（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，以及指导构建体的选择体内评估。