We have shown that administration of a novel anti-CD54 monoclonal antibody (UV3) results in long-term survival of SCID mice bearing human myeloma xenografts. Previous studies have demonstrated a link between the expression of CD54 and the progression of uveal melanoma. Our study assessed the expression of CD54 on 7 human uveal melanoma cell lines and 3 cell lines established from uveal melanoma metastases. In vivo studies examined the efficacy of systemic and local administration of UV3 antibody on the progression of uveal melanoma cells transplanted either heterotopically or orthotopically into SCID mice. Five of the 7 primary uveal melanoma cell lines and all 3 of the metastases cell lines expressed CD54. Intraperitoneal injection of either IgG or F(ab 0 ) 2 fragments of UV3 significantly inhibited the growth of subcutaneous and intraocular melanomas. Subconjunctival injection of either IgG or F(ab 0 ) 2 fragments of UV3 produced a significant reduction in the growth of intraocular melanomas, even if the antibody was administered after the appearance of intraocular tumors. The results indicate that both primary and metastatic human uveal melanoma cells express CD54. The marked inhibition of intraocular and subcutaneous uveal melanoma progression suggests that UV3 antibody is a promising therapeutic agent for further evaluation in patients with uveal melanoma. This is especially noteworthy, as no existing therapeutic modality prevents metastasis of uveal melanoma or prolongs the survival of patients with uveal melanoma. ' 2005 Wiley-Liss, Inc.Key words: anterior chamber; eye; CD54; immunotherapy; uveal melanoma Uveal melanoma is the most common intraocular malignancy in adults and occurs with a frequency of 6 to 7 cases per one million adults. 1 Although cutaneous and uveal melanomas share a neural crest origin, they differ significantly in their epidemiological, 2 cytogenetic 3 , metastatic 4-6 and immunological 4 characteristics. One of the remarkable differences between cutaneous and uveal melanomas is their metastatic behavior. Although skin melanomas metastasize to almost any organ, uveal melanoma displays a propensity to spread to the liver. Indeed, liver metastases are present in up to 95% of the patients who die from uveal melanomas. [7][8][9][10] Although there have been advances in the treatment of primary uveal melanomas, the 5-year survival rate for uveal melanoma patients has not improved in the past 30 years. 1,10 Moreover, no therapeutic modality prevents the metastasis of uveal melanoma or prolongs the survival of patients. 11 Studies have suggested a correlation between the expression of CD54 and the progression of skin and uveal melanomas. 12,13 Expression of CD54 was detected in 81-85% of human uveal melanoma specimens. 13,14 Reduced expression of CD54 in primary uveal melanomas has been associated with increased metastatic disease. 13 CD54 is an important ligand for leukocytes and is believed to be involved in immune surveillance. 15,16 Intravenous administration of MAb against human CD54 (U...

We have previously described the development and testing of a monoclonal anti-human CD54 antibody (UV3) in SCID mice xenografted with human multiple myeloma, lymphoma, and melanoma cell lines. In all 3 cases, UV3 was highly effective at slowing the growth of tumors and/or prolonging survival. Since CD54 (ICAM-1) is up-regulated on many different types of cancer cells, we have now investigated the anti-tumor activity of UV3 in several other CD54 1 epithelial tumors. A panel of 16 human breast, prostate, non-small cell (NSC) lung, and pancreatic tumor cell lines was examined for reactivity with UV3, and 13 were positive. A representative CD54 1 cell line from each cancer was grown subcutaneously in SCID mice. Once the tumors were established, UV3 was administered using different dose regimens. UV3 slowed the growth of all 4 tumors, although it was not curative. When UV3 or gemcitabine were administered to SCID mice xenografted with a NSC lung tumor cell line or a pancreatic tumor cell line, UV3 was as effective as the chemotherapy alone. When gemcitabine and UV3 were administered together, the best anti-tumor responses were observed. UV3 has been chimerized (cUV3) and both toxicology studies and clinical trials are planned to assess the safety and activity of cUV3 in patients with one or more of these tumors.

UV3 is a monoclonal antibody that recognizes human CD54 (intercellular adhesion molecule-1), and it was generated for the therapy of human multiple myeloma. In a severe combined immunodeficient (SCID) xenograft model of human multiple myeloma, UV3 significantly prolonged the survival of mice with either early or advanced stages of disease. However, the mechanism by which UV3 exerted its antitumor effect remained unknown. As reported previously UV3 could mediate antibody-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity in vitro. F(ab)'2 fragments of UV3 had therapeutic efficacy in vivo, suggesting that effector functions were not critical. The purpose of this study was to further define the importance of the Fc portion of UV3 for its antitumor activity in vivo. To this end, we examined the effect of an "ultrapure" preparation of UV3 F(ab)'2 to treat SCID mice xenografted with either ARH-77 cells, a human multiple myeloma cell line, or Daudi cells, a human Burkitt's lymphoma cell line. In addition, we evaluated different doses of UV3 immunoglobulin G (IgG) in these mice to determine the minimum amount of IgG that would produce a therapeutic effect. Data obtained from this study suggest that (1) the Fc portion of UV3 is critical for its antitumor activity in vivo, (2) low levels of UV3 IgG in a preparation of F(ab)'2 fragments account for all of its in vivo activity in multiple myeloma and most of its activity in lymphoma, and (3) UV3 IgG significantly prolongs the survival of SCID/ARH-77 mice as well as SCID/Daudi mice.