Abstract
Abstract 1653
Many non-Hodgkin lymphomas (NHL) and acute lymphoblastic leukemia (ALL) initially respond to therapy, but relapse; at that point further treatment is often limited by chemotherapy-related toxicity. CD22 is a valid target for immunotherapy of NHL and ALL. We have shown that the anti-CD22 ligand blocking monoclonal antibody (mAb), HB22.7, has significant activity. Antibody drug conjugates (ADC) are emerging as the next generation of targeted therapies for lymphoid neoplasms as they may be designed to be effective but with manageable toxicity. We sought to determine if HB22.7 could be used as a platform for CD22-targeted ADCs for the treatment of lymphoid neoplasms. We describe here the effect H22.7-saporin (SAP), a novel ADC composed of HB22.7 and a ribosome inactivating protein on ALL and NHL models.
The in vitro cytotoxicity of HB22.7-SAP was assessed using two pre-B cell ALL lines REH and JM1, and NHL cell lines Ramos, Raji, Granta 519, SU-DHL-4, and DOHH-2. HB22.7-SAP had IC50 values of 0.7 and 1.2 ng/mL in ALL and 1.0–8.4 ng/mL in the NHL cell lines. Free HB22.7 plus SAP did not have any cytotoxic effect using the same doses. HB22.7-SAP was not cytotoxic to CD22 negative Jurkat cells.
To evaluate HB22.7-SAP's in vivo efficacy against a model of human ALL, NOD/SCID mice were injected with REH leukemia cells. Twenty-four hours later the mice were treated with PBS, free HB22.7 plus SAP, or HB22.7-SAP. Treatment was continued twice weekly for 4 weeks. Mice were euthanized at the onset of hind limb paralysis. The median survival was 52 days as compared to 20 days for the untreated mice (p < 0.0005). Mice treated with HB22.7-SAP had normal blood counts over the study period. In contrast, mice from the PBS or free HB22.7 plus free SAP groups developed leukopenia and thrombocytopenia by day 20, coincident with development of ALL; bone marrow from the two mice that developed hind limb paralysis confirmed ALL.
To assess efficacy in a human model of NHL, Raji cells were injected into the flank of previously radiated, female, athymic nude mice. Tumors grew until they reached 100–200 mm3 (day 0). Mice were then exposed to HB22.7-SAP, PBS, or free HB22.7 plus free SAP. Each treatment was administered intraperitoneally, weekly for 3 weeks. To assess significance of starting tumor volume on HB22.7-SAP-mediated tumor growth inhibition, a second model initiated therapy 24 hours after tumor implantation and used the same dose and drug schedule. During the first 14 days, HB22.7-SAP (1 mg/kg) significantly inhibited tumor growth (p < 0.01) on days 5 and 8 as compared to the PBS and free HB22.7 plus free SAP control groups, however, by day 19, the average tumors volume of mice treated with HB22.7-SAP were no different than the controls. In contrast, when HB22.7-SAP was administered 24 hours after subcutaneous injection of Raji cells no mice in the treatment group developed measureable tumors in the 50-day study period. There was no difference in hematologic toxicity between the groups however mice treated with HB22.7-SAP had more therapy-related weight loss.
This study demonstrates the promising in vivo and in vitro activity of HB22.7 when used as a platform for CD22-targeted ADCs. The HB22.7-SAP ADC is both specific and cytotoxic to CD22 expressing malignant lymphocytes and that translates into significant efficacy against NHL and ALL. When compared to other anti-CD22 mAb we hypothesize that HB22.7-based ADCs will prove to be potent cytotoxic drugs in-part due to their unique ability to block ligand binding thus conferring an independent lymphocidal property.
Disclosures:
No relevant conflicts of interest to declare.
Human Monoclonal Antibody-Drug Conjugates in the Experimental Treatment of Malignant Gliomas —Studies In Vitro and In Vivo—