Abstract C164: New tri-glycyl peptide linker offers advantages for maytansinoid antibody-drug conjugates (ADCs)

Autor: Erica Hong, Yulius Setiady, Jennifer A. Coccia, Nathan Fishkin, Ravi V. J. Chari, Yelena Kovtun, Rajeeva Singh, Juliet Bouchard, Hans K. Erickson, Karen Veale, Wayne C. Widdison, Jose F. Ponte, Katharine C. Lai, Andre Dandeneau, Leanne Lanieri, Gregory T. Jones
Rok vydání: 2013
Předmět:
Zdroj: Molecular Cancer Therapeutics. 12:C164-C164
ISSN: 1538-8514
1535-7163
Popis: Clinical-stage ADCs with a maytansinoid cytotoxic moiety (AMCs) currently use either a cleavable, hindered disulfide linker or the non-cleavable, thioether linker, SMCC. Both types of linkers have demonstrated comparative advantages pre-clinically for different cancer targets. Pre-clinically, benefits of the thioether linker can include greater AMC tolerability, while benefits of a hindered disulfide linker can include enhanced AMC activity. A goal of continued linker research is to create additional linker options to achieve the maximal therapeutic window for each AMC developed. We thus designed a new, tri-glycyl peptide linker (CX) which, like the SMCC linker, utilizes lysosomal cleavage of the AMC's antibody component. However, the CX linker provides an additional cleavage site to release a maytansinoid catabolite (MAY) bearing a carboxylic acid that should be largely uncharged at lysosomal pH (4.5) and should more readily diffuse out of the lysosome. To assess if AMCs with the CX linker were more active than those with the SMCC linker, we prepared AMCs (DM1 and 3H-DM1) with each of these linkers (CX-AMC, SMCC-AMC) with an anti-EpCAM and a non-targeting antibody, and compared their pharmacokinetics (PK), in vitro cytotoxic activity, cellular processing, and in vivo efficacy in EpCAM+ cell lines and xenografts. Two types of in vitro cytotoxicity patterns were observed: in one set of cell lines (HT29, COLO 205, OVCAR-3, LOVO) both AMCs were similarly active, whereas in another set (Calu3, A431, CAL27, SW2) the CX-AMC was more active (>5-fold lower IC50) than the SMCC-AMC. In cell lines where the CX-AMC was more active, a 3-fold greater amount of CX MAY was found in medium. This was due to better lysosomal processing (∼10-35% higher) and CX MAY export out of the lysosome, followed by its ultimate export into the medium. CX MAY, negatively charged at physiological pH, was 1000-fold less cytotoxic than a neutral maytansinoid when added extracellularly, suggesting that the CX-AMC would not have bystander killing activity on neighboring cancer cells. The CX-AMC was more cytotoxic against multidrug resistant cells (HCT-15, LOVODOX) than SMCC-AMC. A CX-AMC was prepared with a high load of 8 average DM1 per antibody, which was more cytotoxic than a typical AMC with 4 DM1 per antibody against low-antigen cells in vitro. We compared the efficacy of anti-EpCAM-CX-AMC and SMCC-AMC (4 DM1/antibody) against a Calu3 lung cancer xenograft model in SCID mice. The SMCC-AMC was inactive at the highest tested dose of 15 mg/kg conjugate. In contrast, the CX-AMC was active even at the lowest tested dose of 3 mg/kg, which was about 1/60th of the maximum tolerated dose (MTD). The MTD of CX-AMC was similar to that of SMCC-AMC in mice. Similar PK profiles were observed for CX-AMC and SMCC-AMC in CD-1 mice, indicating that the CX linker is highly stable in circulation. In conclusion, the CX peptide is a promising linker option for AMCs in cancer therapy. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C164. Citation Format: Rajeeva Singh, Nathan Fishkin, Yelena Kovtun, Gregory Jones, Jose Ponte, Hans Erickson, Erica Hong, Yulius Setiady, Andre Dandeneau, Katharine Lai, Jennifer Coccia, Leanne Lanieri, Juliet Bouchard, Karen Veale, Ravi Chari, Wayne Widdison. New tri-glycyl peptide linker offers advantages for maytansinoid antibody-drug conjugates (ADCs). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C164.
Databáze: OpenAIRE
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