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Novel Transgenic Mouse Models Addressing Outstanding Translational Barriers in Antibody-Based Therapeutics

新型转基因小鼠模型解决了抗体治疗中突出的转化障碍

基本信息

批准号：
10658865
负责人：
Stylianos Bournazos
金额：
$ 60.39万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-07 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658865
关键词：
Address Affinity Allogenic Animal Model Antibodies Antibody Response Antibody Therapy Antibody-drug conjugates Binding Biological Biological Models Biological Products Cell Surface Proteins Cells Chemotherapy-Oncologic Procedure Chronic Clinical Data Detection Development Diagnosis Diagnostic Diagnostic Imaging Disease Dose Drug Kinetics Engineering Epitopes Evaluation Exhibits Fc Receptor Fc domain Generations Genes Genetically Engineered Mouse Half-Life Human IgG1 Immune Immune system Immunocompetent Immunoglobulin Constant Region Immunoglobulin G Immunologic Deficiency Syndromes Immunotherapy Knock-in Mouse Leukocytes Macaca Malignant Neoplasms Methods Modality Modeling Monoclonal Antibodies Mouse Strains Mus Natural Killer Cells Neoplasms Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacodynamics Play Population Preclinical Testing Proteins Radioimmunoconjugate Radiolabeled Role Safety Schedule Sensitivity and Specificity Series Surface Testing Therapeutic Therapeutic Monoclonal Antibodies Therapeutic antibodies Toxic effect Toxicology Transgenic Mice Treatment Efficacy Treatment-related toxicity Tumor Antigens Tumor Immunity Xenograft Model anti-cancer therapeutic antibody diagnostic antibody engineering antibody-dependent cell cytotoxicity cancer cell cancer immunotherapy cancer therapy clinical development clinical efficacy clinically relevant cytotoxic efficacy evaluation efficacy testing gene function genetic association genetic variant human monoclonal antibodies humanized mouse imaging study immunogenicity immunoregulation improved in vivo in vivo evaluation in-vivo diagnostics innovation interest mouse model neonatal Fc receptor neoplastic nonhuman primate novel novel therapeutics pre-clinical preclinical development preclinical evaluation preclinical study receptor receptor expression targeted treatment therapeutic evaluation transgene expression translational barrier translational study tumor

项目摘要

ABSTRACT Monoclonal antibodies have played a pivotal role in the diagnosis and treatment of cancer for nearly two decades and continue to grow at an exponential pace. Initially developed for their exceptional ability to target tumor antigens and elicit antibody-dependent cellular cytotoxicity (ADCC), they have more recently been used to modulate a patient’s immune system for anti-cancer immunotherapy. While the generation and development of antibodies targeting various cell surface proteins has rapidly progressed, appropriate model systems for pre- clinical testing of such therapeutics has lagged. This is because human antibodies i) don’t fully engage murine or non-human primate Fc receptors (FcγRs), ii) are foreign proteins that are rapidly rejected in allogeneic hosts and iii) are often inappropriately tested in immunodeficient xenograft models lacking adaptive immune cells or homologous FcγR. Thus, our studies have focused on the generation and testing of clinically relevant models to better understand the in vivo activity of diagnostic and therapeutic antibodies. The current proposal aims to now generate and fully characterize novel murine models that allow better preclinical testing of human antibodies by engineering our previously developed humanized FcγR mouse strains to express human FcRn and IgG1. Expression of human FcRn will allow more accurate pharmacokinetic analysis of human antibodies and assessment of methods aimed at generating antibodies with extended in vivo half-life. By replacing the mouse heavy chain with the constant regions of human IgG1, this model will also allow chronic administration of human IgG-based therapeutics without developing anti-drug antibody responses. By addressing two major hurdles in the field of antibody therapeutics, these models will allow more rapid and efficient pre-clinical toxicology testing and potentially uncover novel mechanisms of Fc-engineered antibodies. Additionally, given the growing interest in immunotherapy, having an immunocompetent model provides an additional advantage over current xenograft models. Finally, as recent data suggest an important role for Fc-FcγR in radiolabeled antibody diagnostics, these models will provide a clinically relevant model to help improve the development and testing of innovative antibody-based molecules for the in vivo detection and localization of neoplasms.

摘要

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Click Chemistry and Radiochemistry: An Update.

DOI：
10.1021/acs.bioconjchem.3c00286
发表时间：
2023-11-15
期刊：
BIOCONJUGATE CHEMISTRY
影响因子：
4.7
作者：
Bauer, David;Cornejo, Mike A.;Hoang, Tran T.;Lewis, Jason S.;Zeglis, Brian M.
通讯作者：
Zeglis, Brian M.

Visualizing Galectin-3 Binding Protein Expression with ImmunoPET.

DOI：
10.1021/acs.molpharmaceut.3c00241
发表时间：
2023-06-05
期刊：
Molecular pharmaceutics
影响因子：
4.9
作者：
Keinänen O;Sarrett SM;Delaney S;Rodriguez C;Dayts EJ;Capone E;Sauniere F;Ippoliti R;Sala G;Iacobelli S;Zeglis BM
通讯作者：
Zeglis BM

IL-15 synergizes with CD40 agonist antibodies to induce durable immunity against bladder cancer.

IL-15 与 CD40 激动剂抗体协同作用，诱导针对膀胱癌的持久免疫力。

DOI：
10.1101/2023.01.30.526266
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Wong,JeffreyL;Smith,Patrick;Angulo-Lozano,Juan;Ranti,Daniel;Bochner,BernardH;Sfakianos,JohnP;Horowitz,Amir;Ravetch,JeffreyV;Knorr,DavidA
通讯作者：
Knorr,DavidA

Click chemistry: a transformative technology in nuclear medicine.

DOI：
10.1038/s41596-023-00825-8
发表时间：
2023-06
期刊：
NATURE PROTOCOLS
影响因子：
14.8
作者：
Bauer, David;Sarrett, Samantha M.;Lewis, Jason S.;Zeglis, Brian M.
通讯作者：
Zeglis, Brian M.

A novel mouse strain optimized for chronic human antibody administration.

DOI：
10.1073/pnas.2123002119
发表时间：
2022-03-08
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Gupta A;Smith P;Bournazos S;Ravetch JV
通讯作者：
Ravetch JV