Monoclonal Antibodies the current scenario

1. Paul Ehrlich introduced the concept of the “Magic bullet” (1900)
2. Pressman and Korngold in 1953 demonstrated that antibodies selectively targeted tumor cells and provided a means of exploiting the immune system by recognizing and directing antitumour responses against defined targets.
3. The therapeutic efficacy of these first generation monoclonal antibodies was limited largely due to their immunogenicity as these were generated from polyclonal antiserum from immunized animals. Recognized as foreign by the innate immune system it was rapidly cleared eliciting inflammatory effects.
4. 1970s -Multiple Myeloma -elaborated immunoglobulins .
5. Neils Jerne, George Kholer and Caesar Milstein in 1975 decided to use the immunoglobulin secreting machinery of the plasma cell for creating monoclonal antibodies. They fused myeloma cells that had lost their secretory capacity with previously immunized healthy B cells with intact secretory potential--The hybridoma--and generated large quantities of monoclonal proteins with high purity and monospecificity for a single epitope. In theory these constructs after binding to the antigen are eliminated by the immune system. Conjugates of these proteins were thought to provide the proverbial “magical bullet” for the treatment of various types of cancer.
6. Antibody based therapeutics elicit cell kill by modulating the immune system to target tumor cell (Cell mediated cytotoxicity Complement dependent cytotoxicity, and immunomodulation) or components of the signal transduction pathways with unconjugated antibodies and those Mo Antibodies not capable of eliciting an immune response are still rendered effective by conjugating them with cytotoxic payloads.1) Immunodrug conjugates- Focused delivery of antibody drug conjugates allows higher dose intensity with minimum normal tissue toxicity e.g.- Gemtuzumab for AML.2) Immunotoxins – Tumor localizations of antibodies targeting internalized antigens coupled with plant/bacterial toxins e.g. antiCD22 Immunotoxins for Burkitt lymphoma xenograft models.3)Radio immuno conjugates –e.g. Ibritumomab and Tositumomab for NHL.5)Immumnocytokine Conjugates- IL2 immuno conjugates enhance T cell mediated immune response to enhance a vascular leak to permit better localization of the antibody. Pre targeted multistep antibody conjugates have been developed with the idea of sparing the toxicity of systemic chemotherapy or the slow delivery of of an immunoconjugate – e.g. ADEPT-Antibody dependent Enzyme Pro drug Therapy.
   Unconjugated antibodies are another class of agents that are finding increasing application in the treatment of solid tumors. 1) Trasutzumab- A humanized antibody which recognizes HER-2 neu ,a member of the EGFR family and which is expressed in more than 25%of all breast cancers. Used in the adjuvant setting it reduces recurrence by 50% after a year of use.2) Cetuximab – This chimeric antibody binds to the domain 3 of the EGFR inhibiting the activation of the tyrosine kinase reception and finds use in the colorectal and squamous cell cancers.3) Panitumab –Blocks the binding of EGFR &TGFa is approved for the treatment of metastatic colorectal cancer relapsing after adjuvant therapy. 4) Rituximab and Alemtuzumab are humanized anti CD20 & anti CD 52 antibodies used in the management of NHL in the adjuvant setting.
   Since the advent of hybridoma technology by Kohler and Milstein, antibody therapy has witnessing a flurry of activity leading to few molecules that have reached the clinic and many more in the pipeline. Judicious application of the clinical and preclinical data is needed for the process to continue and more antibodies are needed to effectively tackle malignant tumors.