YT101 and Other AntiCD5 Antibodies

CD5 (T1, Leu-1), a mature T-cell marker that is also expressed in CLL, is the ligand for CD72, which is expressed on all B-lymphocytes. Evidence suggests that CD5 stimulates splenic B-cell activation and proliferation through its interaction with CD72 on splenic B-lymphocytes (126). Interestingly, in vitro studies showed that crosslinking of CD5 on resting B-lymphocytes, but not on T-lymphocytes, led to apoptosis (127-129). The T101 monoclonal antibody, which recognizes CD5, has been conjugated to 90Y in order to increase its activity against tumor cells. Preclinical studies in human leukemia CEM cells demonstrated that T101 is internalized slowly and undergoes little lysosomal degradation. Instead, T101 undergoes recycling to the cell surface, thus providing a possible explanation for the unmodified antibody's low anti-cancer efficacy (130). Thus, conjugation to a radioisotope was necessary to increase the clinical activity of T101.

In a phase I study, two patients with CLL and eight patients with cutaneous T-cell lymphoma (CTCL) were treated with 5 or 10 mCi of 90Y-T101 (131). Therapy was complicated by development of HAMAs after 1 cycle in 9 of 10 patients. Even though only one patient received a second cycle of therapy, both CLL patients and three CTCL patients achieved PR (50%) with a median response duration of 23 wk. However, significant hematological toxicity was observed, with T-cell and B-cell suppression lasting for 2-3 wk and more than 5 wk, respectively.

Finally, the anti-CD5 monoclonal antibody OKT1 has been conjugated to saporin-6 (SAP), a plant ribosome-inactivating protein. Fresh CLL cells from 31 patients were exposed in vitro to OKT1-SAP. OKT1-SAP inhibited CLL proliferation in 90% of patients; this inhibition was dose-dependent, with a 50% inhibitory concentration (IC50) of 4-7 nM (132).

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