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Background
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.
Alternative Names
Monomethyl auristatin E pAb
References
1. de Goeij BE, et al. New developments for antibody-drug conjugate-based therapeutic approaches. Curr Opin Immunol. 2016 Jun;40:14-23.
2. Fu Z, et al. Peripheral neuropathy associated with monomethyl auristatin E-based antibody-drug conjugates. iScience. 2023 Aug 29;26(10):107778.
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References
Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E-based Antibody-Drug Conjugate for Treatment of Nectin-4-expressing Cancers
Mol Cancer Ther
Authors: Zhou W, Fang P, Yu D, Ren H, You M, Yin L, Mei F, Zhu H, Wang Z, Xu H, Cao Y, Sun X, Xu X, Bi J, Wang J, Ma L, Wang X, Chen L, Zhang Y, Cen X, Zhu X, Lou L, Liu D, Tan X, Yang J, Meng T, Shen J.
Overexpression of nectin cell adhesion protein 4 correlates with cancer progression and poor prognosis in many human malignancies. Enfortumab vedotin (EV) is the first nectin-4-targeting antibody-drug conjugate (ADC) approved by the FDA for the treatment of urothelial cancer. However, inadequate efficacy has limited progress in the treatment of other solid tumors with EV. Furthermore, ocular, pulmonary, and hematologic toxic side effects are common in nectin-4-targeted therapy, which frequently results in dose reduction and/or treatment termination. Thus, we designed a second generation nectin-4-specific drug, 9MW2821, based on interchain-disulfide drug conjugate technology. This novel drug contained a site specifically conjugated humanized antibody and the cytotoxic moiety monomethyl auristatin E. The homogenous drug-antibody ratio and novel linker chemistry of 9MW2821 increased the stability of conjugate in the systemic circulation, enabling highly efficient drug delivery and avoiding off-target toxicity. In preclinical evaluation, 9MW2821 exhibited nectin-4-specific cell binding, efficient internalization, bystander killing, and equivalent or superior antitumor activity compared with EV in both cell line-derived xenograft and patient-derived xenograft (PDX) models. In addition, 9MW2821 demonstrated a favorable safety profile; the highest nonseverely toxic dose in monkey toxicologic studies was 6 mg/kg, with milder adverse events compared with EV. Overall, 9MW2821 is a nectin-4-directed, investigational ADC based on innovative technology that endowed the drug with compelling preclinical antitumor activity and a favorable therapeutic index. The 9MW2821 ADC is being investigated in a phase I/II clinical trial (NCT05216965 and NCT05773937) in patients with advanced solid tumors.
A HER2-targeting antibody-MMAE conjugate RC48 sensitizes immunotherapy in HER2-positive colon cancer by triggering the cGAS-STING pathway
Cell Death Dis
Authors: Wu X, Xu L, Li X, Zhou Y, Han X, Zhang W, Wang W, Guo W, Liu W, Xu Q, Gu Y.
Human epidermal growth factor receptor 2 (HER2) is a protein that is overexpressed in some types of cancer, including breast and urothelial cancer. Here we found that HER2 was present in a portion of colon cancer patients, raising the possibility of using anti-HER2 therapy. RC48, a novel antibody-drug conjugate (ADC) comprising cytotoxic monomethyl auristatin E (MMAE) and an anti-HER2 antibody tethered via a linker, showed a comparable therapeutic effect in both HER2 low expressed (IHC2+/FISH- or IHC+) and high expressed urothelial cancer patients. In vitro studies using colon cancer cell lines showed that RC48 effectively impeded the proliferation of HER2-positive cells, indicating its potential as a treatment for HER2-positive colon cancer. Mechanism study showed that RC48 not only induces cell cycle arrest but also disrupts HER2-mediated restain of cGAS-STING signaling, potentially activating an immune response against the cancer cells. The administration of RC48 significantly reduced the growth of HER2-positive colon cancer and made HER2-positive colon cancer cells more susceptible to immunotherapy. The results of our study will contribute to determining the feasibility of RC48 as a therapeutic option for HER2-positive colon cancer.
COA
Publication 
Figure 1. Considerations for ADC design and development
Figure 2. Chemical structure of MMAE-based antibody-drug conjugates (ADCs)
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