Product details

The chemical name: Immunoglobulin G1, anti-(human receptor tyrosine-protein kinase erbB-2 (EC 2.7.10.1, p185erbB2, MLN 19 or CD340)); humanized mouse monoclonal rhuMab HER2γ1 heavy chain (223-214’)-disulfide with humanized mouse monoclonal rhuMab HER2 κlight chain, dimer (229-229”:232-232”)-bisdisulfide dimer; conjugated on an average of 3 to 4 lysyl, to maytansinoid DM1 via a succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) linker (EMA, 2023)

The antibody trastuzumab

The antibody trastuzumab (anti-HER2 IgG1) is a recombinant humanised monoclonal antibody (rhumAb) that is capable of selectively binding the HER2/p185 (human epidermal growth factor receptor 2) protein which is present in abundance on the surface of breast cancer cells in certain forms of breast cancer.

This selectivity allows Kadcyla to specifically bind to breast cancer cells while ignoring normal healthy cells. Once bound to the HER2 receptor the drug is taken into the cell through receptor-mediated endocytosis. Inside the cancer cell, the ADC is broken down within the lysosome into its substituent parts, releasing a DM1-containing metabolite, lysine-MCC-DM1 (Fu et al., 2022).

Trastuzumab was developed by Genentech in the early 1990s and is directed against the HER2 protein (Carter et al., 1992). Trastuzumab is the active substance in the cancer drug Herceptin, approved in the USA in 1998 and in the EU in 2000, which is used for the treatment of early and metastatic HER2-positive breast cancers as well as metastatic gastric cancers which show HER2 overexpression (EMA, 2024, FDA, 1998).

The cytotoxic drug DM-1

DM1/mertansine, the drug conjugate in Kadcyla is a thiol-containing maytansinoid that was developed by Immunogen Inc. in the 1990s (Chari et al., 1992). Maytansinoids are extremely cytotoxic macrolide natural products, first characterised upon the isolation of maytansine from the East African shrub Maytenus serrata (Kupchan et al., 1972). Maytansinoids have since been found to be produced by bacteria and several bacterial fermentation processes have been developed for the production of various maytansine derivatives, including DM1 (Cassady et al., 2004).

DM1 (Drug Maytansinoid 1) is a C3-ester of maytansine and acts a tubulin inhibitor, interfering with microtubule assembly preceding cell mitosis (Lopus et al., 2010); this leads to cell cycle arrest in the G2/M phase and subsequently, cell death (Khongorzul et al., 2020). DM1 is linked to lysine residues on trastuzumab using a covalent linker molecule MCC (Lewis Phillips et al., 2008). There are, on average, 3.5 DM1 molecules linked to each antibody, i.e., drug-to-antibody ratio (DAR) (EMA, 2023).

The linker molecule MCC

MCC is a non-cleavable, heterobifunctional linker molecule that covalently binds the DM1 drug moiety to trastuzumab. Before the conjugation step, the linker molecule is known as SMCC (N-Succinimidyl 4-[maleimidomethyl] cyclohexane-1-carboxylate).

Kadcyla is produced using a seven step manufacturing process in Lonza’s Visp, Switzerland site. The conjugation consists of two major steps:

1. Linking of SMCC to trastuzumab

2. Conjugation of DM1 to SMCC linkers (EMA, 2023).