Human monoclonal antibodies to immunoglobulin superfamily receptor translocation- associated-3, -4 and -5 molecules as potential therapeutic agents for B-cell malignancies

摘要

B-cell malignancies, which include various forms of leukaemias and lympho-mas as well as multiple myelomas, arise from neoplastic transformation of B-cells at distinct stages of differentiation and result in significant morbidity and mortality. The introduction of therapeutic mAbs against B-cell surface antigens has brought major improvements in disease outcome for several forms of B-cell malignancies. However, a substantial proportion of patients still succumb to these diseases and there is a crucial need for additional reagents directed at novel B-cell surface molecules. Ig superfamily receptor translocation-associated (IRTA) molecules may provide such new targets. IRTA molecules (also called Fc receptor homologues) are cell surface glycoproteins that contain 3 - 9 Ig domains in their extracellular regions and consensus immunoreceptor tyrosine-based activation and/or inhibitory motifs in their cytoplasmic tails. This family of molecules comprises six members, five of which (IRTA-1, -2, -3, -4 and -5) are preferentially expressed during B-cell differentiation. Preliminary evidence indicates that B-cell-associated IRTA molecules are also differentially expressed in various B-cell malignancies. As an approach to exploit the possible therapeutic value of IRTA molecules, Medarex has generated and characterised fully human mAbs with specificity and high affinity for IRTA-3, -4 or -5. These mAbs are claimed to be potentially useful for the treatment of B-cell malignancies, but this remains to be further investigated.