Potent Activity of an Anti-ICAM1 Antibody–Drug Conjugate against Multiple Myeloma
| العنوان: | Potent Activity of an Anti-ICAM1 Antibody–Drug Conjugate against Multiple Myeloma |
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| المؤلفون: | Daniel W. Sherbenou, Thomas G. Martin, Olivia Perez De Acha, Byron Hann, Blake T. Aftab, Megan Murnane, Yang Su, Jeffery L. Wolf, Shelby C. Bearrows, Bin Liu, Christopher R. Behrens |
| المصدر: | Clinical cancer research : an official journal of the American Association for Cancer Research, vol 26, iss 22 Clin Cancer Res |
| بيانات النشر: | American Association for Cancer Research (AACR), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Cancer Research, Immunoconjugates, medicine.medical_treatment, Mice, 0302 clinical medicine, hemic and lymphatic diseases, Monoclonal, Multiple myeloma, Cancer, Tumor, Antibodies, Monoclonal, Hematology, Middle Aged, Intercellular Adhesion Molecule-1, Flow Cytometry, Antibodies, Anti-Idiotypic, Anti-Idiotypic, medicine.anatomical_structure, Oncology, 5.1 Pharmaceuticals, 030220 oncology & carcinogenesis, Heterografts, Female, Development of treatments and therapeutic interventions, Multiple Myeloma, Biotechnology, Adult, Antibody-drug conjugate, medicine.drug_class, Oncology and Carcinogenesis, Monoclonal antibody, Article, Antibodies, Cell Line, 03 medical and health sciences, Rare Diseases, Clinical Research, In vivo, Cell Line, Tumor, medicine, Animals, Humans, Oncology & Carcinogenesis, Cell Proliferation, Aged, business.industry, Daratumumab, Immunotherapy, medicine.disease, ADP-ribosyl Cyclase 1, Orphan Drug, 030104 developmental biology, Cancer research, Bone marrow, business, Ex vivo |
| الوصف: | Purpose: New therapies have changed the outlook for patients with multiple myeloma, but novel agents are needed for patients who are refractory or relapsed on currently approved drug classes. Novel targets other than CD38 and BCMA are needed for new immunotherapy development, as resistance to daratumumab and emerging anti-BCMA approaches appears inevitable. One potential target of interest in myeloma is ICAM1. Naked anti-ICAM1 antibodies were active in preclinical models of myeloma and safe in patients, but showed limited clinical efficacy. Here, we sought to achieve improved targeting of multiple myeloma with an anti-ICAM1 antibody–drug conjugate (ADC). Experimental Design: Our anti-ICAM1 human mAb was conjugated to an auristatin derivative, and tested against multiple myeloma cell lines in vitro, orthotopic xenografts in vivo, and patient samples ex vivo. The expression of ICAM1 was also measured by quantitative flow cytometry in patients spanning from diagnosis to the daratumumab-refractory state. Results: The anti-ICAM1 ADC displayed potent anti-myeloma cytotoxicity in vitro and in vivo. In addition, we have verified that ICAM1 is highly expressed on myeloma cells and shown that its expression is further accentuated by the presence of bone marrow microenvironmental factors. In primary samples, ICAM1 is differentially overexpressed on multiple myeloma cells compared with normal cells, including daratumumab-refractory patients with decreased CD38. In addition, ICAM1-ADC showed selective cytotoxicity in multiple myeloma primary samples. Conclusions: We propose that anti-ICAM1 ADC should be further studied for toxicity, and if safe, tested for clinical efficacy in patients with relapsed or refractory multiple myeloma. |
| وصف الملف: | application/pdf |
| تدمد: | 1557-3265 1078-0432 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7c90915ca7c606383916fa2bf8e189cbTest https://doi.org/10.1158/1078-0432.ccr-20-0400Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....7c90915ca7c606383916fa2bf8e189cb |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15573265 10780432 |
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