Early phase I results of recombinant immunotoxin HA22 in patients with B-cell leukemia

Abstract

3039 Background: HA22 is a 63 kDa recombinant anti-CD22 immunotoxin containing the variable domains of the anti-CD22 Mab RFB4 connected to truncated Pseudomonas exotoxin. HA22 is a mutant form of BL22, which induced CR in 61% of patients with CdA-pretreated hairy-cell leukemia (HCL), and partial or marginal response (PR or MR) in chronic lymphocytic leukemia (CLL). BL22 is much more cytotoxic for HCL compared to CLL ex vivo; the median IC50 is 4.3 ng/ml in 33 patients with HCL vs 430 ng/ml in 70 patients with CLL (p < 0.0001). Compared to BL22, HA22 contains THW replacing SSY in the CDR3 domain of the variable heavy domain, which improves binding affinity to CD22 by 15-fold. CLL cells from 17 patients are a median of 8-fold more sensitive to HA22 than to BL22. Methods: Patients with HCL and CLL were treated on 2 separate multicenter phase I protocols. Eligibility required at least 2 prior standard therapies and a medical indication for treatment including either disease-related cytopenias, symptoms or increasing tumor burden. Patients were treated with HA22 by 30 min infusion every other day for 3 doses (QOD x3), with cycles repeated every 28 days. Dose-escalation in each trial required 0 of 3 or 1 of 6 patients with dose limiting toxicity (DLT) by cycle 2 day 10, or by cycle 1 day 28 if patients were followed without DLT and not retreated. Neutralizing antibodies in the serum and active HA22 in the plasma were quantified by cytotoxicity assays using CD22+ Raji cells. Results: Nine HCL and 11 CLL patients received HA22 at 5, 10, or 20 ug/Kg QOD x3, with no DLT. High levels of neutralizing antibodies were observed in 1 (14%) of 7 HCL and 0 of 7 CLL patients evaluated. In 13 of 14 evaluable patients, peak plasma levels were higher with the 3rd than with the 1st dose (median 1.8-fold, range 0.9–11-fold, p < 0.0001), either due to rapidly decreasing tumor burden or clearing of soluble CD22. The median half-life with the 3rd dose of HA22 was 66 min (range 23–121 min). Despite low dose levels, patients with HCL responded with 1 (20%) CR and 4 (80%) PR in 5 evaluable patients. Patients with CLL have had decreases in circulating CLL cells. Conclusions: HA22 at early dose levels is active in HCL and without significant toxicity in both HCL and CLL. There is no evidence of increased toxicity due to the increased binding of HA22 to CD22. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Medimmune