Toxin-Based Therapeutic Approaches

Shapira, Assaf; Benhar, Itai

In order to target CD25 expressing cells (low-affinity IL2 receptor, see above) regardless of the presence of other IL2R subunits (CD25 is generally expressed to a much greater extent relative to CD122 and CD132 on most malignant cell types [137,138]), PE38 was fused to a single-chain form of the anti-CD25 monoclonal antibody anti-Tac [174] [175] [176] . The resulting immunotoxin, Anti-TacFv-PE38 (LMB-2), demonstrated promising results in pre-clinical trials toward CD25 + cells and tumor xenografts in nude mice [177] [178] [179] . In a Phase I trial, LMB-2 was administrated intravenously to 35 patients with chemotherapy-resistant leukemia, lymphoma and HD, resulting in 1/35 (3%) complete and 7/35 (20%) partial remissions. The most common toxicities included transaminase elevations that were associated with fever, possibly as an outcome of cytokine release. Six of the 35 patients made neutralizing antibodies after one cycle, preventing them from receiving re-treatment [180] [181] [182] . In Phase II trials on patients with metastatic melanoma, administration of LMB-2 has led to a transient partial reduction in circulating and tumor-infiltrating CD25 + T-regulatory (Treg) cells which are able to suppress the ability to vaccinate against self/tumor antigens [183] . However, LMB-2 therapy did not augment the immune response to peptide based cancer vaccines [184] . Other Phase II trials are currently underway in patients with CD25 + Chronic Lymphocytic Leukemia (CLL), Cutaneous T cell lymphoma (CTCL) and Hairy Cell Leukemia (HCL).