4112 CD70 is highly expressed in multiple tumor types including many lymphomas and clear cell renal carcinomas. The expression in lymphomas is not surprising given the role of CD70 in B and T cell activation. However, expression of CD70 at high levels and very high prevalence in renal cancer was initially unexpected. The tightly controlled and limited expression in normal tissues, together with this high level tumor expression makes CD70 an extremely attractive target for antibody-directed therapy. In order to exploit this specificity we have isolated and characterized a human anti-CD70 antibody of high affinity and specificity from transgenic mice. This antibody has been conjugated to highly potent DNA alkylating agents via hydrazone and amino acid based linkers. The resulting CD70 targeted antibody-drug conjugates show potent and curative anti-tumor activity at low doses; highly specific antigen targeting activity (as shown by comparing CD70 antibody conjugates with isotype control conjugates in vivo ), and an extremely wide therapeutic window in both lymphoma and renal cancer models. Furthermore, these CD70 antibody drug conjugates are demonstrating favorable toxicity profiles in larger animals at levels far in excess of the xenograft model determined efficacious doses.

1995 CD70 (CD27L) is a ligand for CD27 mediated co-stimulation of B, T and NK cells. Recently it has been shown that CD70 expression is dramatically and specifically upregulated in clear cell renal cell carcinoma ( ccRCC ) at the mRNA and protein levels. There have also been sporadic reports of increased expression of CD70 in certain types of lymphomas and leukemias. Here we describe fully human anti-human CD70 antibodies derived from transgenic mice that express human immunoglobulin genes. Immunohistochemical analyses using one of these antibodies reveals that CD70 expression is highly prevalent in both ccRCC and Non-Hodgkins lymphomas. FACs analysis, as well as IHC, confirm normal tissue expression in activated B and T cells. We have developed two different strategies to specifically target and destroy CD70 expressing cancer cells. The first uses ADCC and the second a small molecule toxin conjugated to the antibody that is specifically released on internalization in CD70 expressing malignant cells. In vitro and in vivo experiments using both of these mechanisms will be presented.