Antibody–Maytansinoid Conjugates

Antibody–maytansinoid conjugates (AMCs) have emerged as a promising class of targeted cancer therapeutics. By combining the specificity of monoclonal antibodies (mAbs) with the potent cytotoxicity of maytansinoid payloads, AMCs offer a highly effective approach to selectively destroying cancer cells while minimizing damage to healthy tissues. To date, AMCs have been highly favored by researchers and a series of breakthroughs have been achieved.

Introduction to Antibody-Drug Conjugates

Antibody-drug conjugates (ADCs) are a class of targeted cancer therapeutics that combine the specificity of monoclonal antibodies (mAbs) with the cytotoxicity of small-molecule drugs. ADCs consist of three main components: the monoclonal antibody, the linker, and the cytotoxic drug payload. Once the ADC binds to the target antigen on the cancer cell surface, it is internalized through receptor-mediated endocytosis. Within the cancer cell, the linker is cleaved, releasing the cytotoxic drug payload. The released drug then exerts its therapeutic effect, leading to cell death through various mechanisms such as DNA damage, disruption of microtubules, or inhibition of key signaling pathways.

Figure 1. Structure of ADCs.
(Source: Joubert, N. et al., 2020)

Antibody-maytansinoid Conjugates

The use of ADCs significantly increases the therapeutic window of maytansinoids compared to free drugs. One example is T-DM1, which combines the humanized anti-HER2 IgG1 trastuzumab with the microtubule inhibitory drug DM1. T-DM1 has shown significant efficacy against metastatic breast cancer. Two other AMCs, lorvotuzumab mertansine and SAR3419, have shown promising results in early-stage clinical trials for the treatment of B-cell malignancies and solid and liquid tumors expressing CD56 and CD19, respectively.

Current clinical AMCs use several different linkers to link maytansinoids (DM1 or DM4) to tumor-specific humanized antibodies. For example, T-DM1 employs a non-cleavable thioether-based linker, whereas lorvotuzumab mertansine employs a cleavable disulfide-based linker. The chemical versatility of maytansinoid alkaloids allows the use of different linkers, enabling precise control of drug release and enhancing the therapeutic efficacy of these conjugates.

Figure 2. Structures of antibody-maytansinoid conjugates prepared for the current study.
(Source: Sun, X. et al., 2011)

Besides approved AMCs, numerous other conjugates are currently in clinical phases II/III. These conjugates continue to utilize DM1/DM4 as warheads. However, there has been an expansion in the targets being pursued. These targets include FOLR1, CD19, CD138, CD37, CD56, Mesothelin, CA6, and more. The development of these AMCs with a broad range of targets highlights the versatility and potential of AMCs in targeting various cancer types.

Maytansinoid-Related Antibodies

Maytansinoid-Related Antigens

Maytansinoid-Related ELISA Kits