Selection of Subtypes of Antibodies for Tumor Therapy

Selection of Subtypes of Antibodies for Tumor Therapy

Monoclonal antibody (mAb) is an increasingly important drug, of which the clinical application has completely changed the field of cancer treatment. Different monoclonal antibodies have different anti-tumor mechanisms, such as blocking tumor-specific growth factor receptors or immunomodulatory molecules, and complement and cell-mediated tumor cell lysis. Therefore, for many monoclonal antibodies, Fc-mediated effector functions are critical to therapeutic efficacy. Since immunoglobulin subtypes differ in the ability to bind to FCR on immune cells and their ability to activate complement, they activate different immune responses. Therefore, the choice of the antibody subtype depends on its expected mechanism of action. Considering that the clinical efficacy of many monoclonal antibodies is only achieved in small groups of patients, the selection of the best subtype and Fc optimization in the antibody development process may be an important step towards improving the prognosis of patients.

The mechanism of action of tumor antigen targeting antibody

The first generation of therapeutic antibodies approved for clinical use is still the most common type of monoclonal antibody in cancer treatment, consisting of antibodies against tumor antigens. These tumor antigens are more or less important for tumor growth, survival, and invasion, such as anti-HER2 and anti-EGFR. However, some observations in humans and mice indicate that Fc-mediated immune cell activation is an important mechanism of action for many of these monoclonal antibodies.

The Fc part of the antibody can activate effector cells, such as FCR on NK cells, macrophages, or neutrophils, and then mediate tumor cell lysis by cytotoxicity (antibody-dependent cell-mediated cytotoxicity, Adcc) or phagocytosis of tumor cells (antibody-dependent cell-mediated phagocytosis, ADCP). In addition, through its Fc tail, the antibody can activate the complement cascade by binding to C1q, leading to tumor cell lysis through several mechanisms that include the formation of membrane attack complex (MAC), directly inducing the lysis of target cells, or attracting immune cells through the chemotaxis of complement components C3a and C5a.

In addition, C3b and C4b mediate complement-dependent cell-mediated cytotoxicity (CDCC) of NK cells, macrophages/monocytes, and granulocytes, or complement-dependent cell-mediated phagocytosis of myeloid cells (CDCP ). Antibody-mediated cell death can also lead to the release of tumor antigens and the formation of the immune complex (IC), thereby stimulating anti-tumor T cell responses and maintaining tumor control and rejection. In this process, the binding of Fc?Rs and the activation of complement play a key role in the uptake of IC by dendritic cell (DC) and the presentation of tumor antigens.

Optimization of IgG effector functions

IgG-Fc effector functions are mediated by complement and Fc?Rs, which are divided into activation receptors (Fc?RI, Fc?RIIa/IIc, Fc?RIIIa, Fc?RIIIb) or inhibitory receptors (Fc?RIIb). Since most effector cells activate and inhibit Fc?Rs at the same time, IgG binding is a combined result of affinity, receptor availability, and signaling ability. The relative affinity of an antibody to its receptor is defined as the activation/inhibition (A/I) ratio.

Antibodies against immune checkpoints

Theoretically, checkpoint blocking antibodies do not require Fc-mediated effects because their main effector function comes from blocking receptor-ligand interactions. However, in mouse models, functional Fc was found to contribute to the therapeutic effect of anti-CTLA4 checkpoint inhibitors.

Agonist antibodies targeting TNFR

The Fc part of agonistic monoclonal antibodies targeting specific members of the tumor necrosis factor receptor (TNFR) family plays a key role in its therapeutic effect. The target of these monoclonal antibodies is to activate death receptors on tumor cells, such as DR4, DR5 and FAS, to induce cell death, or to activate costimulatory receptors on immune cells, such as CD40, 4-1BB, OX40, GITR, and CD27 to improve the anti-tumor immune response.

The clinical application of mAbs fundamentally changes tumors therapy. It is increasingly apparent that mAbs regulate their effects through a variety of different mechanisms of action, which means that choosing the correct Ig subtype is crucial. Researchers have invested much energy to understand the Fc-mediated effects and Fc modification of different antibody subtypes to further improve the efficacy. In order to optimize Fc-mediated effector functions, a variety of strategies have been developed to provide brand new opportunities for improving antibody-based cancer treatments. In addition, by considering patient-related factors, such as their immune status, the characteristics of TME or Fc?R polymorphisms, Ig subtype selection can allow the development of antibodies that are active in a wider range of patients, or allow the use of antibodies tailored to individual needs. Those considerations may enable us to move towards tailor-made drugs and more effective monoclonal antibody treatments in the future.

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