A103 – The Success Story of an LICR Monoclonal Antibody
In both surgical pathology and cancer research, the correct classification of a neoplastic lesion, with respect to its biology and origin, is crucial. Is a tumor benign or malignant? Is ‘it’ a colon or a lung carcinoma, a sarcoma or a melanoma? Though this appears to be a straightforward undertaking, it is oftentimes not. This is especially true in cases where pathologists and researchers are faced with a metastatic lesion from an unknown primary tumor. Without accurate classification, prognosis and treatment decisions can be catastrophically wrong and cancer researchers are likely draw erroneous conclusions from experiments conducted on those samples.
The mainstay of surgical pathology for many decades has been the ‘H&E’ (hematoxylin-eosin) stain, two chemical dyes used to color tissue sections. Decades ago, H&E and other classical histochemical stains/dyes were used exclusively to elucidate the nature of a neoplastic lesion. Today, immunohistochemistry (IHC) has become an important tool for everyday analysis in surgical pathology and research laboratories. Though techniques using antibodies to detect particular structures had been used on tissue sections for quite some time, the real breakthrough of IHC as a diagnostic and research tool came with the development of monoclonal antibody (mAb) technology by Koehler and Milstein in the late 1970’s. Though in recent years and especially for particular types of tumors, molecular methods such as (RT‑)PCR have gained access to diagnostic labs, IHC is still the most commonly used and widespread diagnostic ancillary technique.
The mAb technology allows the generation of a renewable source of identical antibodies with sharply defined specificity. Also, new IHC techniques, so-called ‘antigen retrieval’ methods, were developed in the early 1990’s to enable the use of mAbs in standard archival material. Until then, the use of many, if not most antibodies seemed to be limited as they did not work in formalin-fixed paraffin-embedded tissues, ‘paraffin blocks’, the standard method of fixing and preserving tissues. IHC and mAbs have truly revolutionized diagnostic surgical pathology and research and are now standard tools for tumor analysis and classification.
In 1994, Dr. Thierry Boon, Director of the Brussels Branch, and his colleagues identified a novel antigen, Melan-A, in the course of defining vaccine targets for cancer immunotherapy using autologous cytotoxic T cell assays in melanoma patients. Molecular analysis indicated that Melan-A was present solely in tissue containing melanocytes. However, mRNA expression does not equal protein expression, and in order to further characterize Melan-A and assess its potential as a vaccine target, an anti-Melan-A mAb seemed mandatory. Consequently, Dr. Lloyd J. Old, Director of the New York Branch and his colleagues, particularly Dr. Yao-Tseng Chen (Affiliate at Cornell University in New York), having long experience in the production of serological reagents, generated a mAb to Melan-A. The new mAb was given the designation A103 by the late Dr. Elizabeth Stockert (New York Branch) who carried out the immunization and fusion procedure.
Pathologist Dr. Achim Jungbluth was recruited to the New York Branch at about that time and tested and developed mAb A103 for use on ‘paraffin blocks’, as standard pathology archival material is commonly called. It turned out that mAb A103, when used with the appropriate antigen retrieval techniques, worked very well in paraffin blocks. Further analyses by Dr. Jungbluth and the closely collaborating dermatopathologist Dr. Klaus Busam from the Department of Pathology at Memorial Sloan-Kettering Cancer Center demonstrated A103’s ability to identify cells and tissues of melanocytic lineage and tumors derived thereof. A103 has now been used for many years within LICR as a tool to analyze the presence of Melan-A in melanoma patients for LICR's Melan-A based cancer vaccine studies and by the wider clinical and research community for the differential diagnosis of melanocytic tumors, especially metastatic tumors.
The LICR Office of Intellectual Property & Licensing (OIP) was first approached in 1997 with a request to license the mAb for use as a research and diagnostic reagent. Today several companies have licenses to sell A103 as part of their research product panel. In the last three years combined sales of A103 by these licensee's have increased at a rate of 50% per annum as the use of the mAb as part of the routine diagnostic armamentarium of many immunohistochemical laboratories has increased.
The story of mAb A103 demonstrates beautifully LICR’s strengths and the success of the Institute’s model. LICR researchers in Brussels identified the Melan-A gene, the A103 monoclonal antibody was generated and characterized by LICR scientists and Affiliates in New York, the antibody was licensed by the LICR Office of Intellectual Property and it is now being used as a screening tool for LICR clinical trials. More importantly, A103 is an example of success with respect to our mission of bringing LICR research discoveries to human benefit. By March 2006, more than 200 scientific publications reported the use of A103 in the biological analysis of Melan-A, melanocytes and melanocytic tumors. A103 has in fact turned out to be a highly valuable reagent for the diagnosis of melanomas and melanoma-related lesions for the oncology community worldwide.
With thanks to Dr. Achim Jungbluth, New York Branch
References
- Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975 Aug 7;256(5517):495-7.
- Coulie PG, Brichard V, van Pel A, Wölfel T, Schneider J, Traversari C, Mattei S, de Plaen E, Lurquin C, Szikora JP, Renauld JC, Boon T (1994) A new gene coding for a differentiation antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med 180: 35-42.
- Chen YT, Stockert E, Jungbluth A, Tsang S, Coplan KA, Scanlan MJ, Old LJ. Serological analysis of Melan-A(MART-1), a melanocyte-specific protein homogeneously expressed in human melanomas. Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5915-9.
- Jungbluth AA, Busam KJ, Gerald WL, Stockert E, Coplan KA, Iversen K, MacGregor DP, Old LJ, Chen YT. A103: An anti-melan-a monoclonal antibody for the detection of malignant melanoma in paraffin-embedded tissues. Am J Surg Pathol. 1998 May;22(5):595-602.
- Busam KJ, Chen YT, Old LJ, Stockert E, Iversen K, Coplan KA, Rosai J, Barnhill RL, Jungbluth AA. Expression of melan-A (MART1) in benign melanocytic nevi and primary cutaneous malignant melanoma. Am J Surg Pathol. 1998 Aug;22(8):976-82.
- Busam KJ, Iversen K, Coplan KA, Old LJ, Stockert E, Chen YT, McGregor D, Jungbluth A. Immunoreactivity for A103, an antibody to melan-A (Mart-1), in adrenocortical and other steroid tumors. Am J Surg Pathol. 1998 Jan;22(1):57-63.