An Anti-CD72 Immunotoxin Against Therapy-Refractory B-Lineage Acute Lymphoblastic Leukemia

Abstract

CD72 is a broadly expressed B-lineage specific surface antigen. We used J3-109(anti-CD72) monoclonal antibody to examine primary neoplastic cells from patients with acute leukemia for CD72 expression. CD72 was present at high levels in 70 of 100 B-lineage acute lymphoblastic leukemias (ALL), but it was not expressed on cells from 23 T-lineage ALL patients or 9 acute myeloblastic leukemia patients. We have prepared an anti-CD72 immunotoxin by conjugating J3-109 monoclonal antibody to the ribosome-inactivating protein, PAP. J3-109-PAP effectively killed > 99.9% of clonogenic blasts from a CD72⁺ B-lineage ALL cell line. We used a SCID mouse model of aggressive human pre-B ALL to evaluate the in vivo anti-leukemic efficacy of the J3-109-PAP immunotoxin. An intravenous challenge with 1 × 10⁶NALM-6-UM-1 (pre-B ALL)cells caused 100% of SCID mice to die of disseminated leukemia within 41 days. Importantly, a three-day treatment with non-toxic doses of J3-109-PAP significantly improved event-free survival of SCID mice. The Kaplan-Meier estimate (± standard error) of the probability of event-free survival at 2 months after inoculation of NALM-6-UM-1 cells was 40 ± 16% for SCID mice treated with a total of 15 μg J3-109-PAP (median survival = 58 days) as compared to 0 ± 0% for PBS treated mice (median survival = 34 days). At 6 months after the inoculation of NALM-6-UM-1 cells, 10 ± 9% of the J3-109-PAP treated SCID mice were still alive with no evidence of leukemia. In contrast to J3-109-PAP, the control immunotoxin G17.2 (anti-CD4)-PAP, at a total dose of 15 or 30 μg showed no anti-leukemic activity against the NALM-6-UM-1 cells. Thus, J3-109-PAP immunotoxin was effective against human pre-B-ALL and, to our knowledge, this report is the first description and characterization of an anti-CD72 immunotoxin.

Key Words:

• Anti-CD72 Immunotoxin
• refractory leukemia
• B-ALL