A Novel HER2-targeted Antibody–drug Conjugate Offers the Possibility of Clinical Dosing at Trastuzumab-equivalent Exposure Levels
| Autor: | Stepan Chuprakov, Fangjiu Zhang, Yun Cheol Kim, David Rabuka, Dominick Yeo, Robyn M. Barfield, Penelope M. Drake, Ayodele O. Ogunkoya, Mark D. Pegram, Maxine Bauzon, Colin Hickle |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
musculoskeletal diseases
0301 basic medicine Drug congenital hereditary and neonatal diseases and abnormalities Cancer Research Antibody-drug conjugate Immunoconjugates Maximum Tolerated Dose Receptor ErbB-2 media_common.quotation_subject medicine.medical_treatment Breast Neoplasms Pharmacology Ado-Trastuzumab Emtansine Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Pharmacokinetics In vivo Trastuzumab Cell Line Tumor medicine Animals Humans Potency Maytansine Dosing skin and connective tissue diseases media_common Chemotherapy business.industry Xenograft Model Antitumor Assays Rats Macaca fascicularis 030104 developmental biology Oncology 030220 oncology & carcinogenesis Female business medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics. 19:1866-1874 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-20-0190 |
| Popis: | Trastuzumab and the related antibody-drug conjugate (ADC), ado-trastuzumab emtansine (T-DM1), both target HER2-overexpressing cells. Together, these drugs have treatment indications in both early-stage and metastatic settings for HER2+ breast cancer. T-DM1 retains the antibody functionalities of trastuzumab and adds the potency of a cytotoxic maytansine payload. Interestingly, in the clinic, T-DM1 cannot always replace the use of trastuzumab plus chemotherapy administered together as single agents. We hypothesize that this failure may be due in part to the limited systemic exposure achieved by T-DM1 relative to trastuzumab because of toxicity-related dosing constraints on the ADC. We have developed a trastuzumab-based ADC site-specifically conjugated to maytansine through a noncleavable linker. This construct, termed CAT-01-106, has a drug-to-antibody ratio (DAR) of 1.8, approximately half the average DAR of T-DM1, which comprises a mixture of antibodies variously conjugated with DARs ranging from 0-8. The high DAR species present in T-DM1 contribute to its toxicity and limit its clinical dose. CAT-01-106 showed superior in vivo efficacy compared to T-DM1 at equal payload dosing and was equally or better tolerated compared to T-DM1 at equal payload dosing up to 120 mg/kg in Sprague-Dawley rats and 60 mg/kg in cynomolgus monkeys. CAT-01-106 also showed improved pharmacokinetics in rats relative to T-DM1, with 40% higher ADC exposure levels. Together, the data suggest that CAT-01-106 may be sufficiently tolerable to enable clinical dosing at trastuzumab-equivalent exposure levels, combining the functions of both the antibody and the payload in one drug and potentially improving patient outcomes. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|