Abstract 587: Superior anti-tumor effects of an anti-HLA-DR IgG4 antibody, IMMU-114, in chronic and acute lymphocytic leukemia (CLL and ALL): Comparison to anti-CD20 therapy, chemotherapy, or combined with kinase inhibitors
Authors: Cardillo Thomas M. , Zalath Maria , Arrojo Roberto , Sharkey Robert M. , Goldenberg David M. 
Published: July 2016

Abstract
Purpose: IMMU-114 is a humanized anti-HLA-DR IgG4 monoclonal antibody currently under investigation for non-Hodgkin's lymphoma and CLL (ClinicalTrials.gov, NCT01728207). This study was undertaken to continue preclinical evaluations in CLL and ALL models, comparing IMMU-114 efficacy to anti-CD20 or doxorubicin therapy, respectively, as well in combination with Bruton's tyrosine kinase (Btk) or phosphoinositide-3-kinase (PI3K) inhibitors in CLL.
Procedures: The human CLL cell line, JVM-3, was grown s.c. in SCID mice. Once tumors reached ∼0.2 cm3, they were divided into treatment groups of either IMMU-114 or rituximab (200, 100, or 50 μg, twice weekly for 4 weeks). Study survival endpoint was tumor progression to &gt;1.0 cm3. In vitro, JMV-3 was treated with various concentrations of either a Btk inhibitor (ibrutinib) or PI3K inhibitor (idelalisib) in the presence of a constant amount of IMMU-114. IC50-values were determined, data were normalized, and isobolograms generated for each inhibitor to determine overall effect. For ALL, MN-60 cells were injected i.v. into SCID mice. After 5 days, animals received IMMU-114 (50 or 25 μg, 2 x weekly for 4 weeks) or doxorubicin (3×20 μg qdx3d induction phase, followed by a 60μg bolus injection maintenance phase on week 3). Disease progression was declared upon the onset of hind-limb paralysis.
Results: Mice with JVM-3 tumors had a median survival time (MST) of 14 days for saline controls, while therapy with rituximab significantly improved survival (P&lt;0.0102); the MST was only 19 days for the two highest doses. In contrast, mice treated with IMMU-114 had a MST ≥42 days for all three doses tested (P&lt;0.0001), providing an overall superior tumor growth control over rituximab (P&lt;0.0116). In vitro, an additive effect was observed in JVM-3 when IMMU-114 was combined with either ibrutinib or idelalisib. In the ALL disseminated MN-60 disease model, mice were refractory to the doxorubicin treatment, succumbing to disease at the same rate as saline controls (MST = 23 and 21 days, respectively). Importantly, IMMU-114, at both the 50 and 25 μg doses, provided a significant survival benefit compared to both saline control and doxorubicin-treated animals (MST&gt;39 days, P&lt;0.0001). IMMU-114 therapy was well tolerated in all these studies, as evidenced by no significant loss in weight.
Conclusions: In a preclinical model of human CLL, IMMU-114 was superior to anti-CD20 therapy using rituximab, and had an additive effect when combined with Btk or PI3K inhibitors. IMMU-114 also achieved a significant survival benefit in the doxorubicin-refractive MN-60 ALL model. These data demonstrate IMMU-114's overall activity in diverse hematopoietic cancers and show the need for continued clinical and preclinical evaluation.
Citation Format: Thomas M. Cardillo, Maria Zalath, Roberto Arrojo, Robert M. Sharkey, David M. Goldenberg. Superior anti-tumor effects of an anti-HLA-DR IgG4 antibody, IMMU-114, in chronic and acute lymphocytic leukemia (CLL and ALL): Comparison to anti-CD20 therapy, chemotherapy, or combined with kinase inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 587.