Monoclonal Antibody Therapy

Monoclonal Antibody Therapy

Monoclonal antibody therapy involves the utilization of monoclonal antibodies (mAb) to selectively bind to target cells or proteins, thereby potentially stimulating the patient's immune system to combat those cells. There is extensive ongoing research and development aimed at creating monoclonals for various severe diseases like rheumatoid arthritis, multiple sclerosis, and different cancer types.

These antibodies can be tailored to target almost any extracellular or cell surface marker. There are diverse methods in which mAbs can be employed for therapy, such as destroying malignant tumor cells and impeding tumor growth by obstructing specific cell receptors. One such variant is radioimmunotherapy, where a radioactive dose localizes on the target cell line, delivering lethal chemical doses.

Immunoglobulin G (IgG) antibodies are large heterodimeric molecules, weighing approximately 150 kDa, and are comprised of two distinct polypeptide chains: the heavy (~50 kDa) and the light chain (~25 kDa). Light chains exist in two types, kappa (κ) and lambda (λ). Through cleavage with the enzyme papain, the Fab (fragment-antigen binding) part can be separated from the Fc (fragment constant) part of the molecule. Fab fragments contain the variable domains, housing three hypervariable amino acid domains responsible for antibody specificity, embedded into constant regions. There are four known IgG subclasses, all implicated in Antibody-dependent cellular cytotoxicity.

The immune system reacts to environmental factors by discerning between self and non-self. Tumor cells are not directly targeted by the immune system since they originate from the patient's own cells. However, tumor cells often exhibit abnormal antigens or cell surface receptors that are rare or absent on healthy cells. Examples include ErbB2, which is overexpressed on approximately 30% of breast cancer tumor cells, known as HER2 positive breast cancer.

Antibodies play a crucial role in the adaptive immune response, aiding in the recognition of foreign antigens and triggering an immune response. Monoclonal antibody technology has enabled the development of antibodies against specific antigens presented on tumor surfaces. Immunotherapy emerged following the discovery of antibody structure and the advent of hybridoma technology, which facilitated the production of monoclonal antibodies. Initially, MAb therapy showed limited success, particularly with blood malignancies, and treatment had to be tailored to each patient, proving impractical for routine clinical use.

Advancements in monoclonal drug development led to the creation of four major antibody types: murine, chimeric, humanized, and human. Initial therapeutic antibodies were murine analogues, which faced challenges such as short half-life, limited penetration into tumor sites, and inadequate recruitment of host effector functions. These issues were addressed with the development of chimeric and humanized antibodies, replacing murine antibodies in modern therapeutic applications. Recombinant DNA technology, transgenic mice, and phage display have supplanted hybridoma technology, while understanding proteomics has been crucial in identifying novel tumor targets.