Anti-MMAE polyclonal antibody

Antibody-drug conjugates (ADCs) are chemically linked by tumor-targeted monoclonal antibodies (mAb) and high cytotoxic payloads, which contribute to the precise delivery of cytotoxic agents to cancer cells. Monomethyl auristatin E (MMAE) is a commonly used payload in the development of ADC drugs, which is used in 5 of the 15 approved ADC drugs. After ADC recognizes and binds the target antigen expressed on the cancer cell surface, it is internalized by endocytosis, and then releases the payload through proteolysis/acid cleavage, thus achieving precise killing. By interacting with tubulin, MMAE can inhibit the formation of microtubules and destroy the assembly of mitotic spindles, thus making tumor cells stagnate in the M phase of the cell cycle.

Figure 1. Considerations for ADC design and development
(Source: de Goeij BE, et al. 2016)

MMAE-based ADCs have shown significant efficacy in improving overall treatment outcomes in a variety of cancers. For example, brentuximab vedotin in patients with CD30-positive Hodgkin's lymphoma and systemic anaplastic large-cell lymphoma showed overall objective response rates (ORR) of 73% and 86%, respectively. In solid tumors, enfortumab vedotin is highly effective in the treatment of locally advanced or metastatic uroepithelial cancer. It significantly prolonged median overall survival and median progression-free survival compared to other chemotherapy regimens. In addition, tisotumab vedotin has shown promise in the treatment of patients with recurrent or metastatic cervical cancer. It has an ORR of 24% and a median duration of response of 8.3 months.

Figure 2. Chemical structure of MMAE-based antibody-drug conjugates (ADCs)
(Source: Fu Z, et al. 2023)

However, ADC drugs have non-targeted toxic adverse reactions, and the mechanism is not completely clear. The free payload may have been cytotoxic after treatment of the linker drug by target cells or the tumor microenvironment, resulting in neutropenia or thrombocytopenia. Studies have found that ADC with MMAE payload is potentially toxic to the nervous system and has a high risk of peripheral neuropathy, which covers a range of peripheral nervous system diseases, including weakness, numbness, and pain. The occurrence of peripheral neuropathy may lead to prolonged infusion time or reduced doses, which harms the therapeutic effect and the quality of life of patients. In severe cases, peripheral neuropathy can even endanger the life of the patient.

Monomethyl auristatin E pAb