Therapeutic antibodies are usually homogenous preparations of monoclonal IgG1 monomers with identical protein sequences in order to ensure the desired biological effect in a consistent manner. In addition to specific receptor targeting and longer half-life in blood, the IgG class of antibodies exhibit effector functions that is now being tapped as a major therapeutic mode of action for clinical efficacy. Some of the key mechanisms of action (MoAs) exploited in antibody therapeutics are described here:
The antibody can bind to the receptor on the target cell in an antagonistic fashion. The mAb can inhibit an undesired signaling pathway by blocking ligand-binding or interfering with the di/trimerization process to bring about the preferred physiological effect. For example, the mAb-ligand binding can give rise to inhibition of proliferative signals, blockade of immune checkpoints, induction of pro-apoptotic programs or re-sensitization of cell to a cytotoxic agent. Bispecific antibodies can target two ligands simultaneously so as to block redundant pathways.
Fc mediated response occurs when the target cell is opsonized with the several mAb drug molecules. The Fc region can bind to various molecules eliciting a cytotoxic response which can be via
(i) Antibody-dependent cell-mediated cytotoxicity (ADCC) – The Fc domain can bind to FcγRIIIA on NK cells triggering cell destruction via lytic factors secreted by the NK cells.
(ii) Complement‐dependent cytotoxicity (CDC) – The C1q subunit of the C1 compliment factor binds to the Fc domain initiating a signalling cascade that finally leads to the formation of a membrane attack complex (MAC), a pore that causes cell lysis.
(iii) Antibody-dependent cellular phagocytosis (ADCP or ADPh) – FcγRI expressed on macrophages, neutrophils, and eosinophils can bind to the Fc domain resulting in phagocytosis.
Here, the mAb-receptor binding activates a desired cellular pathway which is, in most cases, the activation of immune cells. Agonism of co-stimulatory ligands on T-cells and dendritic cells are currently being explored as an anti-cancer therapeutic strategy.
It is the main moA utilized by ADCs. Binding of the ADC to the target cell leads to endocytosis of the mAb complex, enabling intracellular delivery of the drug resulting in cell death. Certain payloads have the ability to diffuse and kill surrounding cells, a phenomenon termed as “bystander killing” which is useful in the case of solid tumors.
Most of the therapeutic antibodies elicit more than one of these pharmacological actions. Therefore, while developing mAb therapeutics, it is crucial to thoroughly evaluate the biological activity in-vitro and in in-vivo models using appropriate reference mAbs.