Cancer-specific conjugated monoclonal antibodies for anticancer therapy

Abstract

Abstract

In the last two decades there is substantial development in the diagnostic and therapy of many types of cancers by using monoclonal antibodies. Efficient treatment can be achieved due to ability of antibody to recognize specific antigen expressed on the surface of the tumor cell. Even more significant improvement can be done with conjugation of the antibodies by certain molecules with pharmacological potential.

Cancer-specific monoclonal antibodies are synthesized proteins designed to recognize specific antigens on the surface on the cancer cells. They have ability to activate humoral and cellular immune mechanisms that can modulate tumor growth and metastasis. In addition, specific conjugated monoclonal antibodies can provide selective delivery of cytotoxic substance or radioactive isotope directly to the cancer cell.

In the design of the therapeutic monoclonal antibody several factors have to be considered: specificity of antibody, selection of adequate cytotoxic substance or radioactive isotope, and conjugation method. Optimizing those factors increase potency, specificity, safety and stability of the therapeutic and increase therapeutic index (relationship between the minimal effective dosage and maximal toxic dosage). Additional factor that affects the efficiency of the therapy is the mechanism of releasing of cytotoxic molecule from the antibody into the cytosol of the cancer cell. Upon intravenous administration, Antibody Drug Conjugates (ADC) bind to their target antigens and are internalized through receptor- mediated endocytosis. This facilitates the subsequent release of the cytotoxin, which eventually leads to apoptosis of the cancer cell. Approved ADCs, brentuximab vedotin and trastuzumab emtansine, have demonstrated their effect against haematological and solid malignancies. Antibody-based therapies, both unconjugated antibodies and radioimmunotherapy, have had a significant impact on the treatment of non-Hodgkin lymphoma.  The approved anti-CD20 radioimmunoconjugates (90-Y-ibritumomab tiuxetan or 131-I-tositumomab) have encouraging results, with new ongoing efforts for incorporation of radioimmunoconjugates in various settings.

Conjugated monoclonal antibodies are superior to the conventional approach of cancer treatment regarding to the safety and efficiency. This was confirmed with preclinical and clinical examinations. FDA approves several monoclonal antibodies based on the data of preclinical and clinical examinations and treatment of hematological cancers. In addition, significant numbers of ongoing trials are in phase of clinical examinations.

Generation of more specific antibodies, developing advanced methods of conjugation and explorations of novel anticancer molecules should be the future in therapy of other types of cancer. Improvement of target selection and development of new linkers will be great success of ADCs in strategy for overcoming drug resistance in cancer cells. Concerning this issues, ADCs are likely to be future of targeted anticancer therapy.

KEYWORDS:  anticancer therapy, anti-CD20 antibody, cytotoxic drug, monoclonal antibody, radioimmunoconjugates