Abstract 4334: A novel linker to enable alcohol-containing payloads for the preparation of antibody-drug conjugates

Abstract

Abstract Antibody-drug conjugates (ADCs) have emerged as important therapeutics for treating cancer as evidenced by the recent FDA approval of brentuximab vedotin Adcetris™ and trastuzumab emtansineKadcyla™, and the large number of ADCs (>35) currently in clinical trials. ADCs are composed of two core units: the targeting antibody and the drug-linker. The drug-linker typically consists of a cytotoxic payload, a moiety for covalent attachment to the antibody, and a conditionally cleavable linker that is stable in circulation but releases the cytotoxic payload upon internalization into a target cell. The released payload will possess a residual chemical functional group that is used for attachment of the drug to the cleavable linker. Functional groups that have been exploited within the ADC field for this purpose include amines (primary and secondary), thiols, and carboxylic acids. Unfortunately, many potential ADC payloads do not possess any of these functional group ‘handles’ that allow for stable conjugation and release of the drug in an unmodified form. Use of these payloads often requires modification of the drug structure to introduce a handle for conjugation. To avoid this, we have developed new linker chemistry, the methylene-alkoxy-carbamate (MAC), which enables direct conjugation of drugs through alcohol functional groups. Such groups are present on a diverse array of synthetic drugs and cytotoxic natural products, thus, expanding the potential chemical space available for payload selection. As proof-of-concept, we have linked Auristatin E through the secondary alcohol of the norephedrine residue and characterized the stability and in vivo activity of the resulting ADCs. To further define the potential applicability of the MAC unit, we have examined its stability and release properties with a series of model systems including primary, secondary, and tertiary alcohols as well as a phenol. We have also explored the effect of substitution of the MAC nitrogen on these properties. This novel linker chemistry is currently being applied to new payloads that were inaccessible with previous technology. Citation Format: Robert V. Kolakowski, Karl Haelsig, Scott Jeffrey, Peter Senter. A novel linker to enable alcohol-containing payloads for the preparation of antibody-drug conjugates. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4334.