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The true relevance of a cancer target can only be determined in the context of an effective drug that affects human disease through the target molecule. Ancillary studies, though important, do not accurately predict the usefulness of a drug specific to a target, or the usefulness of a particular target for drug development. This is especially true in the case of monoclonal antibody therapy for cancer. The exquisite specificity of an antibody can result in multiple antibodies which affect different epitopes of the same antigen, potentially producing opposite results. CD44 is an example of such an antigen where both the expression of variants and the use of antibodies targeting different epitopes have produced pleiomorphic effects. ARH460-16-2 is an antibody that targets a glycosylated, conformation-dependent epitope of CD44, with functional activity in vitro. In the MDA-MB-231 heterotopic model of an established breast cancer, the in vivo administration of ARH460-16-2 produced a survival benefit as great as Cisplatin compared to an isotype control. The epitope recognized by ARH460-16-2 is expressed in up to 74% of a variety of human cancers and up to 64% of breast cancers as determined by immunohistochemistry. While the prevalence of this epitope is comparable to other CD44 variants in cancer, the distribution of this epitope on non-cancer cells is more restricted. Therefore, this specific epitope of CD44 is druggable and relevant in a wide population of cancers. This example lends support to the idea that validation of a cancer target can only be considered complete when it enables the discovery of a drug intended for that disease.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]