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Dual Mechanisms of Novel CD73-Targeted Antibody and Antibody-Drug Conjugate in Inhibiting Lung Tumor Growth and Promoting Antitumor Immune-Effector Function
- Source :
- Molecular cancer therapeutics. 19(11)
- Publication Year :
- 2020
-
Abstract
- Although tyrosine kinase inhibitor therapy and immunotherapy have significantly improved lung cancer management, many patients do not benefit or become resistant to treatment, highlighting the need for novel treatments. We found elevated CD73 expression to be prevalent in non–small cell lung cancer (NSCLC) including those harboring the RAS- or RTK (EGFR, EML4-ALK) oncogenes. CD73 expression is enriched closely with the transcriptome signature of epithelial–mesenchymal transition and the immune-tolerant tumor microenvironment, which are increasingly relevant for disease progression and therapy resistance. We developed two novel series of CD73 antibody, Ab001/Ab002 and humanized version Hu001/Hu002, which demonstrated high CD73 binding affinity, potent enzyme inhibition, and efficiently protected effector T lymphocyte function from adenosine/cancer-imposed toxicity. Hu001/Hu002 inhibited growth of RAS-mutant NSCLC tumors in mice via enhanced antibody-dependent cell-mediated cytotoxicity and multifaceted remodeling of the tumor immune environment, reflecting diminished levels of tumor-associated macrophages, myeloid-derived suppressor cells, and tumor vasculature. A novel MMAE-conjugated CD73-ADC (Hu001–MMAE) elicited potent cytotoxicity against CD73-high expressing tumor cells (IC50
- Subjects :
- 0301 basic medicine
Cancer Research
Epithelial-Mesenchymal Transition
Immunoconjugates
Lung Neoplasms
medicine.medical_treatment
T-Lymphocytes
GPI-Linked Proteins
Effector T-Lymphocyte
03 medical and health sciences
Mice
0302 clinical medicine
Immune system
Antineoplastic Agents, Immunological
Glioma
Cell Line, Tumor
medicine
Tumor Microenvironment
Animals
Humans
Molecular Targeted Therapy
Lung cancer
Cytotoxicity
5'-Nucleotidase
Cell Proliferation
Tumor microenvironment
biology
Dose-Response Relationship, Drug
Neovascularization, Pathologic
business.industry
Receptors, IgG
Immunotherapy
medicine.disease
Xenograft Model Antitumor Assays
Disease Models, Animal
030104 developmental biology
Treatment Outcome
Oncology
030220 oncology & carcinogenesis
Gene Knockdown Techniques
biology.protein
Cancer research
Antibody
business
Subjects
Details
- ISSN :
- 15388514
- Volume :
- 19
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Molecular cancer therapeutics
- Accession number :
- edsair.doi.dedup.....0430c24470d360a1cae7d83bab8c95eb