Therapeutic antibodies in oncology: an immunopharmacological overview

Abstract

The biotechnological development of monoclonal antibodies and their immunotherapeutic use in oncology have grown exponentially in the last decade, becoming the first-line therapy for some types of cancer. Their mechanism of action is based on the ability to regulate the immune system or by interacting with targets that are either overexpressed in tumor cells, released into the extracellular milieu or involved in processes that favor tumor growth. In addition, the intrinsic characteristics of each subclass of antibodies provide specific effector functions against the tumor by activating antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis, among other mechanisms. The rational design and engineering of monoclonal antibodies have improved their pharmacokinetic and pharmacodynamic features, thus optimizing the therapeutic regimens administered to cancer patients and improving their clinical outcomes. The selection of the immunoglobulin G subclass, modifications to its crystallizable region (Fc), and conjugation of radioactive substances or antineoplastic drugs may all improve the antitumor effects of therapeutic antibodies. This review aims to provide insights into the immunological and pharmacological aspects of therapeutic antibodies used in oncology, with a rational approach at molecular modifications that can be introduced into these biological tools, improving their efficacy in the treatment of cancer.

Keywords: Antibody-drug conjugates; Bispecific T-cell engagers (BiTEs); Bispecifics; Cancer therapy; Immunobiotechnology; Immunotherapy; Monoclonal antibodies.

Fig. 1

A Structure of therapeutic monoclonal antibodies (TmAbs). Human IgG (top) is formed by two heavy chains and two light chains linked to each other by disulfide bonds, which originate Fab and Fc fragments. Fab fragment contains the antigen-binding site formed by complementary-determining regions (CDRs). The Fc fragment is responsible for effector functions and binds to the neonatal receptor. The single-chain fragment variable (scFv) structure is composed of the variable domains of heavy and light chains. The structure of heavy chain-only antibodies (HcIgG) from camelids (bottom) includes their respective variable domains (VHH), which are being used in the design of TmAbs. B Mechanism of action of TmAbs. i Blockage of immunoregulators (CTLA-4, PD-1, or PDL-1), cytokines or growth factors. The antibody binds to its target expressed on the tumor cell membrane and prevents its interaction with its ligand; ii complement activation-dependent cytotoxicity (CDC). Complement molecule C1q directly interacts with target-bound IgG C_H2 domain, resulting in the activation of the complement cascade and the formation of the membrane attack complex, which induces cell lysis. iii Antibody-dependent cellular cytotoxicity (ADCC). FcγRIIIa (CD16a), a low-affinity activation receptor present on Natural Killer (NK) cells, binds to target-bound IgG1 C_H2 domain. Activation of CD16 triggers the release of perforin and granzymes, resulting in target cell death. iv Antibody-dependent cellular phagocytosis (ADCP). ADCP is mediated through the interaction of the Fc domain of target cell-bound IgG with FcγRs on phagocytic cells, such as tumor-associated macrophages (TAM). FcγRI (CD64) and FcγRII (CD32) recognize overlapping but not identical sites in the lower hinge region of IgGs, which promotes tumor cell phagocytosis. v Antibody-dependent cellular trogocytosis (ADCT). Neutrophils can remove tumor cell surface content in the presence of TmAbs targeting specific cell membrane proteins through Fc binding to FcγR on the effector immune cell, which may trigger tumor cell lysis. vi Antibody–drug conjugate (ADC) and radioimmunoconjugate (RIC). Antineoplastic drugs or radioactive elements can be conjugated to the antibody through a peptide linker to be directed to the target tissue, increasing its cytotoxic concentration in situ and decreasing its unwanted effects on other tissues. vii,viii Bispecific molecules. vii Bispecific antibodies. They have dual binding sites that bind two different antigens. viii Bispecific T-cell engager (BiTE). They are recombinant proteins composed of two scFvs linked by a short flexible linker. These bispecific molecules are designed to target tumor antigens and CD3, thereby creating a link between tumor cells and T cells. Created with Microsoft® PowerPoint for Mac. Version 15.32 and Prism 6 for Mac OS X

Fig. 2

WLA-approved TmAbs and their targets for the treatment of solid and hematological tumors. A Cell-membrane molecules on T lymphocytes (LT), antigen-presenting cell (APC) and tumor cell associated with T cell activation (TCR, CD3, CD4/8, MHC-I/II, CD80/86), T cell inhibition (immune checkpoint molecules CTLA-4, PD-1, PD-L1, Gal-3, LAG-3), and therapeutic antibodies that block immune checkpoint. B and C Specific TmAbs that target immune checkpoint molecules that regulate T cell function. D TmAbs that bind to tyrosine kinase receptors of the ErbB family proteins. E TmAbs and their corresponding targets expressed on B lymphocytes (LB), multiple myeloma cells. Hodgkin lymphoma, systemic anaplastic large cell lymphoma (CD30), acute myeloid leukemia (CD33), and mycosis fungoides or Sézary syndrome (CCR4). F IFN-g, a soluble target involved in hemophagocytic lymphohistiocytosis (HLH) syndrome, can be targeted by a TmAb. G TmAbs that bind to cell surface molecules expressed on neuroblastoma cells and other types of solid tumors. The number in each target indicates the number of WLA-approved therapeutic antibodies for that target. The origin-dependent suffix letter is indicated in bold: Antibody is fully murine (-omab), chimeric (-ximab), humanized (-zumab), or fully human (-umab or -mab). IgG subclasses and modifications incorporated into TmAb design and their respective conjugated drugs are indicated. Afucosylated or low-fucose antibodies improve FcγRIIIa binding and ADCC; aglycosylated (N297A) block Fc effector functions; hinge stabilizing (S228P) is a IgG4 chain mutation to increase the binding between heavy chains (HCs), similar to IgG1. Antibody-conjugated molecules are indicated, including monomethyl auristatin E and F (MMAE and MMAF, respectively), calicheamicin, pyrrolobenzodiazepines (PBD), deruxtecan (DXd), emtansine (DM4), and govitecan (SN38). The radioactive compound yttrium-90 (Y⁹⁰) is a radioimmunotherapeutic (RIT) drug. Bispecific antibodies, such as epcoritamab bind, concomitantly, to tumor cell targets and CD3 on T lymphocytes (LT). CD: Cluster of differentiation; PD-1: Programmed cell death protein 1, PD-L1: Programmed cell death ligand 1, CTLA-4: Cytotoxic T lymphocyte antigen 4, MHC: Major histocompatibility complex, Gal-3: Galectin-3 protein, LAG-3: Lymphocyte activation gene 3, VEGFA: Vascular endothelial growth factor A, HER2: Human epidermal growth factor receptor 2, VEGFR2: Vascular endothelial growth factor receptor 2, PDGFRα: Platelet-derived growth factor receptor α, BCMA: B cell maturation antigen, expressed primarily on B cells, but especially on multiple myeloma plasma cells; IFN-γ: interferon-gamma; SLAMF7: CD319 surface antigen. FRα: Folate receptor alpha; Hz: Humanized; scFv: Single-chain fragment variable; TCR: T cell receptor. Created with Microsoft® PowerPoint for Mac. Version 15.32 and Prism 6 for Mac OS X