Role of Monoclonal Antibodies (mAbs) in Cancer Therapy

Introduction

For the first time in 1890, Behring and Shibasaburo describe antibodies as a neutralizing material in blood in an experimental animal model of Corynebacterium diphtheria causing diphtheria. Heidelberger and Avery stated that antibodies are protein molecules which are having the ability to recognize specific antigens. Further, Astrid Fagraeus observed the production of antibodies by plasma B-cells in 1947. The clonal selection theory (single B-cell clone forms one specific antibody) was proved by Sir Gustav Nossal. Therefore, the monoclonal antibodies (mAbs) are produced by a single clone of a unique B cell which binds to the specific site of an antigen (Ag) called an epitope (antigenic determinant).

Production of monoclonal antibodies

The Methods for the production of monoclonal antibodies include human-mouse hybrid cells, first identified in the year 1973 by Schwaber. Such cells were utilized by Köhler and Milstein in order to produce human-derived hybridomas and after which, research in the field of utilization of mAbs in cancer treatment has started. The first human trial of mAb therapy against cancer was conducted in a lymphoma patient in 1980 but this trial was not considered as successful due to its immunogenic nature in humans. These antibodies were also reported as poor inducers of immunity in patients and hence, limited their applicability. In order to get rid of such limitations, new techniques were introduced to humanize antibodies in the late 1980s. The continuous efforts and advancement in this field led to the emergence of “fully-human” antibodies by using transgenic mice or in vitro yeast or phage which results in the use of such antibodies in cancer treatment.

Antibodies can work in such a way that on one hand, they can kill tumor cells while, on the other hand, they can engage with the immune system of the host and elicit anti-tumor immune responses, simultaneously. This specific approach and multi-directional action make the mAb treatment of choice.

The basic structure of antibody

Antibodies belong to the immunoglobulin (Ig) superfamily. They are large glycoproteins molecules that play a vital role to maintain immunity. Antibodies can recognize as well as neutralize the foreign substance called antigens. Antibodies are denoted as ‘Y’ shaped structures consisting of two heavy (H chain) and two light chains (L chain) held together by a disulfide bridge. Each tip of the Y contains a fragment antigen-binding (Fab) portion which involves in the recognition process of a specific antigen. Further, the base of Y is having another region called fragment crystallizable (Fc) which acts as a mediator to establish the interactions between an antibody and other components of the immune system. On the basis of the presence of the H chain, antibodies can be categorized into five different classes namely, IgG (immunoglobulin gamma), IgA (immunoglobulin alpha), IgM (immunoglobulin mu), IgD (immunoglobulin delta), and IgE (immunoglobulin delta). Among all the antibodies, IgG is the most commonly used for therapeutic purposes due to its ability to mediate specific functions such as Ab-dependent cellular cytotoxicity (ADCC) and C-dependent cytotoxicity (CDC). IgG can be subdivided into four classes namely, IgG1, IgG2, IgG3, and IgG4 in which, only IgG1 and IgG3 are capable to elicit ADCC and CDC. Monoclonal antibodies are antibodies which derived from a single clone and target a specific epitope present on the surface of an antigen.

 

Mechanism of action of mAbs

There are several methods by which mAb can act on tumor cells. The blocking of growth factor receptor signaling (GFRS) is considered one of the important and direct mechanisms through which mAbs can induce death of the tumor cells. The interaction of the different components of the immune system and CDC, antibody-dependent cellular phagocytosis (ADCP), and ADCC are some prerequisites for the indirect action of mAbs.

Antibodies bind to the specific antigens present on the surface of the target cell by means of their fragment antigen binding (Fab) region. The effector cells get attached to the antibody by their Fc region. The host effector cells must express FcR (fragment crystallizable receptor) on their surface with which antibodies will bind to promote ADCC. Natural killer cells (NK cells) are considered the most important effector cells to facilitate ADCC. However, some other myeloid cells like neutrophils, macrophages, monocytes, and eosinophil cells are also involved in ADCC. The release of cytotoxic granules, Fas signaling, and generation of ROS (reactive oxygen species) are some mechanisms through which effector cells cause the death of the target cell.