Development Of Lmb2 For The Treatment Of Cd25 Malignancies

The interleukin 2 receptor (IL-2R) is composed of a(CD25), P(CD122), and 7(CD132) chains. IL-2 binds with high affinity (Kd ~ 10 11 M) to the complex containing all three of them, but with low affinity (Kd ~ 10-8 M) to CD25 alone, also called p55 or Tac.54 In contrast, the mAb anti-Tac binds to CD25 with high affinity (Kd ~ 10~10 M).55 CD25 is overexpressed in a variety of hematologic malignancies, including adult T-cell leukemia (ATL) and HCL, other T- and B-cell leukemias and lymphomas, and Hodgkin's disease.56-58 CD25 usually far outnumbers other subunits of the IL-2R on cells, and in some tumors is the only IL-2R subunit present. To construct an anti-CD25 recombinant immunotoxin, the variable heavy domain of anti-Tac (VH) was fused to the variable light domain via a 15-amino-acid linker to the variable light domain (VL), which in turn was fused to PE40.59 Both anti-Tac(Fv)-PE40 and the slightly shorter derivative anti-Tac(Fv)-PE38 (Figure 33.1) bound well to CD25, and were very cytotoxic to CD25+ cell lines and activated human T cells, which mediate autoimmune disease.5960 LMB-2 induced complete regression of CD25+ human xenografts in mice61,62 and killed fresh leukemic cells from patients with ATL,60,62 HCL, and other leukemias.63 In monkeys, LMB-2 caused reversible transaminase elevations, but not death, at dose levels up to 1000 ^g/kg q.o.d. X 3.6264 Large-scale production of LMB-2 was accomplished after expression of a DNA plasmid in Escherichia coli.65~67

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