Bispecific Antibodies Progression in Malignant Melanoma

Abstract

The discovery of oncogenes and immune checkpoints has revolutionized the treatment of melanoma in the past 10 years. However, the current PD-L1 checkpoints lack specificity for tumors and target normal cells expressing PD-L1, thus reducing the efficacy on malignant melanoma and increasing the side effects. In addition, the treatment options for primary or secondary drug-resistant melanoma are limited. Bispecific antibodies bind tumor cells and immune cells by simultaneously targeting two antigens, enhancing the anti-tumor targeting effect and cytotoxicity and reducing drug-resistance in malignant melanoma, thus representing an emerging strategy to improve the clinical efficacy. This review focused on the treatment of malignant melanoma by bispecific antibodies and summarized the effective results of the experiments that have been conducted, also discussing the different aspects of these therapies. The role of the melanoma epitopes, immune cell activation, cell death and cytotoxicity induced by bispecific antibodies were evaluated in the clinical or preclinical stage, as these therapies appear to be the most suitable in the treatment of malignant melanoma.

Keywords: bispecific antibody; cytotoxicity; immunotherapy; intracellular target; melanoma.

FIGURE 1

Tumor-targeted immunomodulators. The immunosuppressive tumor microenvironment of melanoma. Bispecific antibodies exert anti-tumor effects by binding to tumor-specific antigens (CSPG4/MC1R) and PD-L1, or to double immune checkpoints (RANKL and PD-1) on the surface of T cells.

FIGURE 2

Tumor-targeted death. Tumor drug resistance is due to the prevention of the initiation or execution of the cell death signal. Bispecific antibodies bind to the tumor-specific antigen (MCSP) to activate the death signaling pathway (DR5) and FcγR-carrying immune cells.

FIGURE 3

Engaging immune cells. The malignant melanoma microenvironment hinders the transport, infiltration and activation of T cells. CD3 related Bispecific antibodies bind tumor-specific antigen (HER2, MCSP, MICA, B7-H3, CD43s, and Glycoprotein 100), potentially promoting the intratumoral infiltration and response of T cells.

FIGURE 4

Regulation of intracellular targets. Cell membranes are impermeable to most macromolecules. 3E10-3G5 bispecific antibody retains cell-penetrating and MDM2-binding activities, increases tumor p53 expression, and inhibits the growth of tumors.