Monoclonal Antibodies and Derivatives: Therapeutic Tools for Cancer

The production of murine monoclonal antibodies (mAbs) with defined specificity in 1975 marked the subsequent revolution of cancer therapy. mAbs have been essential to characterize the functional features of molecules involved in cancer cell growth and dissemination. The murine mAbs have been modified to create humanized antibodies and, subsequently, fully human antibodies for cancer therapy, thereby avoiding the side effects of xenogenic protein. The antibody-drug conjugates (ADCs) increased the antitumor effect of mAbs. We will analyze the functional features of ADCs that recognize the cluster differentiation (CD)30 receptor present on some lymphomas and the human epidermal growth factor receptor (HER)2 on solid tumors. The anti-CD30 brentuximab vedotin and the anti-HER2 trastuzumab deruxtecan are two paradigmatic examples to understand the rationale of using mAbs against cancer. Some of the advantages, disadvantages, and clinical applications of these ADCs will be considered. The therapy with antibody derivatives, such as bispecific antibodies (BsAbs) and chimeric antigen receptor (CAR) cells for either CD30 or HER2, increased the potency and efficacy of specific targeting. Therapeutic antibodies directed to other members of the HER2 family, such as EGFR, or to immune checkpoint molecules, such as Programmed-death receptor (PD)-1 and PD-ligand (L) 1, will be analyzed for their ability to shape the tumor microenvironment (TME). Some mentions of functional features of mAbs linked to molecular glue degraders or stabilizers will be analyzed to highlight the potential evolution of ADCs to deliver undruggable molecules. As mimetics of antibodies, the affibodies will be briefly considered to give a more comprehensive scenario of the therapeutic tools that can target a molecule specifically. Overall, this review summarizes the evolution of antibody-based cancer therapeutics, focusing on the mechanistic underpinnings and clinical progress of ADCs, BsAbs, and CAR therapies, while highlighting emerging strategies to overcome resistance and modulate the TME.