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A Novel HER2-targeted Antibody–drug Conjugate Offers the Possibility of Clinical Dosing at Trastuzumab-equivalent Exposure Levels
- Source :
- Molecular Cancer Therapeutics. 19:1866-1874
- Publication Year :
- 2020
- Publisher :
- American Association for Cancer Research (AACR), 2020.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 15388514 and 15357163
- Volume :
- 19
- Database :
- OpenAIRE
- Journal :
- Molecular Cancer Therapeutics
- Accession number :
- edsair.doi.dedup.....eb6c34d486576f054d4a1ee8a2e10261