权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Targeting EMP2 for the treatment of triple negative breast cancer with novel anti-EMP2 Granzyme B immunoconjugates

使用新型抗 EMP2 颗粒酶 B 免疫缀合物靶向 EMP2 治疗三阴性乳腺癌

基本信息

批准号：
9810531
负责人：
Khalid A Mohamedali
金额：
$ 21.84万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9810531
关键词：
Affinity Animals Antibodies Apoptosis Binding Biodistribution Biological Markers Breast Cancer Model Breast Cancer therapy Cancer Diagnostics Cause of Death Cell Death Cell Death Process Cell Proliferation Cell surface Cells Chimeric Proteins Clinic Cytoplasm Cytotoxic agent Data Diagnosis Disease Dose Drug Kinetics Endometrial Engineering Epithelial Evaluation Female Genital Neoplasms Generations Goals Granzyme Growth Factor Half-Life Human IgG1 Immunoconjugates Immunoglobulin G Immunotoxins In Vitro Individual Kinetics Lead Length Link Magic Malignant Neoplasms Maximum Tolerated Dose Membrane Proteins Modeling Molecular Monoclonal Antibodies Mus Neoplasm Metastasis Normal tissue morphology Ovarian Pattern Positioning Attribute Primary Neoplasm Production Protein Engineering Proteins Reagent Recombinant Antibody Recombinants Research Resistance Science Serine Protease Specificity Testing Therapeutic Therapeutic Index Time TimeLine Toxic effect Toxin Tumor Burden University of Texas M D Anderson Cancer Center Woman Work Xenograft procedure alpha Toxin base cancer therapy chemotherapy comparative efficacy cytotoxic cytotoxicity design dosage drug candidate efficacy testing glycosylation immunogenicity improved in vivo indexing malignant breast neoplasm mammary epithelium neoplastic cell new therapeutic target novel novel therapeutics pre-clinical preclinical study protein expression research clinical testing targeted treatment triple-negative invasive breast carcinoma tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Immunoconjugates are designed to focus the delivery of highly cytotoxic agents to specific target cells using monoclonal antibodies, potentially improving the therapeutic index of the agent. To this end, we propose to deliver a cytotoxic protein payload with an anti-EMP2 IgG1 antibody. EMP2, or epithelial membrane protein-2, is a biomarker that is highly expressed in the majority (63%; n=97) of invasive breast cancer tumors examined compared to healthy mammary epithelium, and high EMP2 expression is observed in over 75% of triple negative breast cancer cases examined where EMP2 is observed in both the primary tumor as well as in metastatic lesions. As engineered recombinant antibodies hold great promise for cancer diagnostics and therapy, we have carefully assembled a research team centered at UCLA and The University of Texas MD Anderson Cancer Center to develop recombinant anti-EMP2 antibodies fused to the human serine protease granzyme B for therapy. The group at UCLA has previously shown that a full length IgG1 against EMP2 promotes apoptosis both in vitro and in vivo in a number of EMP2 positive tumors, but as new data suggests that the anti-EMP2 IgG1 can internalize rapidly, we hypothesize that it may serve as a novel candidate for drug conjugation. The use of Granzyme B (GrB) as an immunoconjugate has been proposed as a “magic bullet” as, once delivered to the cytoplasm of a cell, it activates apoptosis pathways with little to no induction of immunogenicity. The Mohamedali lab has utilized human GrB as an effective payload for the generation of recombinant cell death-inducing fusion proteins and has clearly demonstrated that GrB-containing fusion constructs have impressive and highly selective cytotoxic effects when delivered to the cytoplasm by either antibody or growth factor cell targeting carriers. In this proposal, with the explicit goal of advancing the science of anti-EMP2 antibodies as well as GrB as a cytotoxic payload for clinical testing, we will create and determine the efficacy of two anti-EMP2 IgG1- GrB conjugates. Accordingly, the specific aims propose to design and test the efficacy of GrB linked to an anti-EMP2 IgG1 for cytotoxicity as well as start creating a preclinical package to understand its functional affinity and stability. As the naked antibody cross-reacts between human and mouse, the toxicity profile of the immunoconjugate, including pharmacokinetics and maximum tolerated dosage, will also be determined. Given its high expression in a number of gynecological tumors including ovarian and endometrial, these studies will be important to position EMP2 as a viable target for cancers in women. It will also, given the need for new toxins with low immunogenicity, help position granzyme B in the forefront of antibody linked toxins.

项目总结/文摘