Campath1hanticd52 Antibody

CD52 is a nonmodulating glycosylphosphatidylinosi-tol-linked protein that is expressed, in abundance, on normal and malignant B and T lymphocytes, mono-cytes, macrophages, and eosinophils, but not on hematopoietic progenitor cells.124 125 Given the high expression of CD52 on the surface of malignant cells, specific antibody targeting this antigen may serve as appropriate novel therapy for these CD52-expressing tumors. Campath-1H is a genetically engineered human IgG1 anti-CD52 monoclonal antibody, consisting of the hypervariable regions of the parental rat antibody inserted into the framework domains of normal human immunoglobulin IgG1 genes. As a humanized antibody, Campath-1H may work through a number of mechanisms, including complement-mediated lysis, antibody-dependent cell cytotoxicity, and apop-tosis. Different cell types express different levels of CD52 on their surface, which may explain in part the observed variation in their sensitivity to Campath-1H-mediated lysis.126 Campath-1H treatment is generally well tolerated, with the most significant toxicity being prolonged lymphopenia associated with opportunistic infections, especially in heavily pretreated patients.

Prior to the development of Campath-1H, a predecessor antibody, the rat antibody Campath-1G caused clearance of malignant cells from the blood and bone marrow in various lymphoid malignancies, suggesting potential clinical applications for anti-CD52 antibody therapy.127 In a subsequent phase II study involving 39 patients with T-PLL, all but two patients of whom had received prior therapy with a variety of agents, investigators obtained an overall response rate of 76%, with 60% CR and 16% PR.128 The median disease-free interval was 7 months (range 4-45 months). Clearance of tumor cells from the blood and bone marrow was generally rapid but did not cause tumor lysis syndrome. Disease resolution from skin, spleen, and lymph nodes also occurred in approximately half of the affected patients, although those with bulky lymph node masses, serous effusions, or hepatic or central nervous system involvement had more resistant disease. There was a statistically significant difference in survival for patients achieving a CR (median 16 months) as compared to partial responders (median 9 months) or non-responders (median 4 months). Meanwhile, 12 patients were retreated with Campath-IH following relapse, with five (42%) achieving a second CR and one achieving PR, with responses lasting 5-6 months. Seven patients received high-dose therapy with autol-ogous stem cell support, and stem cells harvested from these patients were free of T-PLL cells as documented by flow cytometry and PCR studies. Three of these patients remained alive in CR at 5, 7, and 15 months following autograft. Four additional patients underwent allogeneic stem cell transplants, with three being alive in CR up to 24 months following allograft. As expected, major toxicities were prolonged lymphopenia and opportunistic infections. In a retrospective analysis of compassionate use of the drug for relapsed or refractory T-PLL, 76 patients treated with Campath-IH had an overall response rate of 51% including a 39.5% CR rate, with the median duration of CR being 8.7 months (range 0.13+ to 44.4 months) and median time to progression for all patients being 4.5 months (range 0.1-45.4 months).129 These figures are very favorable in this population whose response rate to first-line chemotherapy was only 32%, with a 6% CR rate and a median time to progression of only 2.3 months (range 0.2-28.1 months). Specific organ CRs varied: 39% in the bone marrow, 33% in the spleen, 32% in lymph nodes, 30% in the liver, and 43% in the skin. Campath-1H also had activity in patients with advanced CTCL. A phase II multicenter study was done in Europe, which enrolled previously treated patients with low-grade NHLs, including CTCL.130 Out of the eight patients with MF, there were four respon-ders (50%), including 2 CRs. This response rate was higher than the 14% response rate (six of 42 patients had PR) seen with the B-cell lymphoma patients under study. Among the four responding MF patients, the median time to progression was 10 months (range 2-14 months). Consistent with previous findings, the most pronounced antitumor effect was seen in blood, bone marrow, and skin, while there was low response with bulky lymph nodes and splenomegaly.

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