Ado-trastuzumab Emtansine (T-DM1): An Antibody–Drug Conjugate (ADC) for HER2-Positive Breast Cancer

Abstract

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that combines the antitumor properties of the humanized anti-human epidermal growth factor receptor 2 (HER2) antibody, trastuzumab, with the maytansinoid, DM1, a potent microtubule-disrupting agent, joined by a stable linker. Upon binding to HER2, the conjugate is internalized via receptor-mediated endocytosis, and an active derivative of DM1 is subsequently released by proteolytic degradation of the antibody moiety within the lysosome. Initial clinical evaluation led to a phase III trial in advanced HER2-positive breast cancer patients who had relapsed after prior treatment with trastuzumab and a taxane, which showed that T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine. In 2013, T-DM1 received FDA approval for the treatment of patients with HER2-positive metastatic breast cancer who had previously received trastuzumab and a taxane, separately or in combination, the first ADC to receive full approval based on a randomized study.

IMGN853, a Folate Receptor-α (FRα)–Targeting Antibody–Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FRα-Expressing Tumors

“…ADCs offer the potential to combine the favorable pharmacokinetics, biodistribution, and tumor-targeting properties of antibodies with the potent cell killing mechanism provided by the attached small molecule, or payload. Clinical validation of this concept has been achieved with the regulatory approval of two ADCs, brentuximab vedotin for relapsed/refractory Hodgkin disease and anaplastic large cell lymphoma and ado-trastuzumab emtansine for recurrent human epidermal growth factor receptor 2 (Her2)-positive breast cancer (21)(22)(23)(24). The latter conjugate consists of the HER2-targeting antibody, trastuzumab, conjugated by the thioether linker, SMCC, to the maytansinoid, DM1.…”

A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity

“…Tumor-selective delivery through linkage of the cytotoxic agent to monoclonal antibodies directed toward tumor-associated antigens affords a means of lowering the nonspecific toxicity of highly potent drugs, while improving their antitumor activity (7)(8)(9)(10)(11). This antibody-drug conjugate (ADC) technology has been validated following the FDA approval of: (i) brentuximab vedotin, a conjugate of an anti-CD30 antibody with the dolastatin derivative, monomethyl auristatin E (12) and (ii) ado-trastuzumab emtansine (T-DM1), a conjugate of trastuzumab with the potent maytansinoid DM1 (13,14). The realization that ADCs offer a means of reviving compounds that were on their own too toxic to be clinically useful has resulted in burgeoning interest in medicinal chemistry efforts to identify suitable "payloads" for use in ADCs.…”

A New Triglycyl Peptide Linker for Antibody–Drug Conjugates (ADCs) with Improved Targeted Killing of Cancer Cells

“…An ADC consists of three components: a monoclonal antibody that binds selectively to an antigen, a cytotoxic payload that inhibits essential cellular functions, and a linker that connects the two while ideally facilitating the intracellular release of the payload from the conjugate. Two ADCs are currently approved by the FDA: (1) brentuximab vedotin (Adcetris), consisting of an anti-CD30 antibody linked to a monomethyl auristatin (MMAE) payload, and (2) adotrastuzumab emtansine (Kadcyla), consisting of the anti-HER2 antibody trastuzumab linked to a maytansinoid (DM1) payload (3,4). In addition, about 50 ADCs targeting numerous antigens are currently being tested in the clinic against hematologic malignancies and solid tumors (5).…”

“…The ADCs typically contain an average of about 4 molecules of a cytotoxic payload linked per antibody molecule, referred to as DAR, although some ADCs have a higher number of approximately 6 to 8 molecules linked per antibody (3,4,6,7,9). The payload molecules are attached at lysine or cysteine residues of the antibody via a linker moiety.…”