3.3.2. Monoclonal Antibodies

The first monoclonal antibodies (mAb) to be clinically tested as a cancer treatment were murine mABs, but their problems of administration in humans limited their clinical usefulness [83]. The success of mAbs therapy came with the development of techniques that allowed the genetic modification of murine mAb to produce murine–human chimeric mAb or humanized mAb, which behaves like human IgG.

These antibodies have some advantages, such as their specific binding to molecular epitopes, interaction with the effector arms of the immune system, their long half-life, the ability to distribute themselves in the intra- and extravascular compartments and that the host tolerates IgGs well as therapeutic agents. In addition, they can be produced in large quantities and at a controlled cost. Due to their effective bio-distribution, systemic mAbs levels last for weeks or months, mediating a prolonged anti-cancer response. mAb can attack tumour cells by binding to tumour-associated antigens (TAAs) and modifying signalling or directing immune effector mechanisms to those tumour cells [84].

There is currently a wide diversity of mAb-based strategies for cancer therapy. The optimal characteristics for a targeted tumour antigen depend on the mAb to be used, the nature of the tumour and the mechanism of action of these mAb.

mAbs that target cell surface antigens can induce apoptosis by direct transmembrane signalling, by complement-mediated cytotoxicity or by inducing antibody-dependent cell cytotoxicity [85,86]. Determining the most appropriate mechanism for each mAb depends on the clinical scenario and is a continuous scientific challenge.

mAb could induce tumour cell death by target cell signalling. However, resistance can arise when cells with alternative or compensatory signalling pathways appear. The use of combination therapy may overcome these resistances. An example is mAbs against the ErbB family of receptors and their ligands, such as Trastuzumab and Pertuzumab [87,88]. The mechanism of these mAbs is complex, as the receptors can have multiple ligands and mAbs can alter the dimerization properties, interfering in different signalling depending on whether it is directed to a homodimer or heterodimer receptor [84].

For mAbs measuring complement-mediated cytotoxicity (CMC), it is known that their ability to bind complement and induce CMC depends on the antigen concentration, membrane orientation and whether the antigen is in monomer or polymer form. CMC also depends on the mAb isotype and the characteristics of the target cell. Some of these mAbs are anti-CD20, in chronic lymphocytic leukemia (CLL), such as rituximab or obinutuzumab. CMC contributes most to the effect of mAb in hematological malignancies, where target cells are exposed to complement system in the circulation [89].

mAbs can also induce antibody-dependent cell cytotoxicity (ADCC), mediated by FcR binding, which is expressed by immune effecting cells such as NK, granulocytes and monocytes/macrophages [90, 91]. The mAb binds to the target cell through FcR, which activates intracellular signals through immunoreceptor tyrosine-based activation motifs (ITAM) and induces the activation of the effector cell, thus producing ADCC.

Many of the tumour associated antigens (TAAs) are not expressed on the surface of the tumour cells but are presented by MHC molecules. Therefore, mAbs have been developed that recognize these peptides, which come from intracellular oncoproteins. These antibodies are restricted by MHC and are still under development and further characterisation [84].

Molecule-specific mAbs that have an impact on the host can block tumour angiogenesis, preventing tumour growth, or target immune checkpoints, enhancing the anti-tumour immune response. In the first case, the mAb that blocks angiogenesis is bevacizumab, which blocks vascular endothelial growth factor (VEGF). This has an anti-tumour effect, as it prevents the passage of nutrients and oxygen to the tumour [92]. As these mAbs do not directly target the tumour, they are usually combined with cytotoxic agents [93]. Bevacizumab is effective in colorectal, lung, breast, renal, brain and ovarian cancer. The mAbs targeting immune checkpoints are described in a following section.

Antibody-drug immunoconjugates and radio-immunoconjugates that deliver a toxic load to tumour cells may also be used. Bi-functional antibodies and Chimeric Antigen Receptor T cells (CAR-T cells) can take advantage of the specificity of mAb to guide the cellular immune system to tumour cells [84]. Therefore, improved mAb-based therapeutic agents are being developed with multiple possibilities in cancer immunotherapy.
