Subcutaneous Injections of IMMU-114 (Anti-HLA-DR IgG4 Monoclonal Antibody): Initial Results of a Phase I First-in-Man Study in Hematologic Malignancies
Authors: Stephens Deborah M. , Starodub Alexander N , Byrd John C , Horne Heather , Wegener William A , Goldenberg David M , Christian Beth A 
Published: October 2019

Abstract
Introduction. HLA-DR is expressed in non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and other B-cell malignancies at significantly higher levels than typical B-cell markers, including CD20. Prior attempts to develop anti-HLA-DR antibodies in this population have been hampered by toxicity, notably infusion-related toxicities (Lin et al, Leuk Lymphoma, 2009). In preclinical studies, a novel anti-HLA-DR IgG4 antibody, L243, was consistently more cytotoxic than rituximab in the cell lines studied, with minimal CDC and ADCC, but activating internal signaling and inducing apoptosis via the AKT survival pathway (Stein et al, Blood, 2006 & 2010). After demonstrating safety in canine lymphoma (Stein et al, Leuk Lymphoma, 2011), this Phase I first-in-man study was undertaken to evaluate IMMU-114 (humanized L243) administered via subcutaneous (SQ) injection in patients with B-cell NHL or CLL.
Methods. Eligible patients had recurrent/relapsed NHL/CLL with at least one prior therapy, ECOG performance status <3, normal baseline renal and liver function, with platelets ≥ 50,000/mm3 and ANC ≥ 1000/mm3. Cohorts of 3-6 patients received 200 mg IMMU-114 administered once-, twice-, or thrice-weekly for the first 3 weeks of a 4-week cycle. All patients received 2 consecutive treatment cycles, followed 4 weeks later by elective maintenance therapy (one week of treatment every 4 weeks x 4). NCI-CTCAE v. 4.0 was used to grade adverse events (AEs). Treatment response was assessed 4 weeks after cycle 2, then every 3 months until progression, using 2007 IWG-NHL or 2008 IW-CLL criteria.
Results. Eleven patients (46-80 years old) with 2 median prior treatments (range, 1-5; all had received rituximab) have now been treated at dose level (DL) 1 (200 mg weekly, n=3), 2 (400 mg weekly, n=5), and 3 (600 mg weekly, n=3). They had diffuse large B-cell lymphoma (DLBCL, n=5); follicular lymphoma (FL, n=3); CLL (n=1), small lymphocytic lymphoma (SLL, n=1), or marginal zone lymphoma (MZL, n=1). Administration reactions were limited and all were Grade 1-2 events, predominantly injection site erythema. No serious adverse events (SAEs) occurred at DL1 or DL2, but at DL3, one DLBCL patient with unrelated anorexia/hypovolemia withdrew prior to cycle 2 with acute renal failure and fatal gastrointestinal bleeding and one MZL patient developed fatal septic shock after completing cycle 2. Safety laboratories were unremarkable and there has been no evidence of human anti-IMMU-114 antibodies in 5 patients currently evaluated. Circulating leukemic cells in the single CLL patient decreased with each cycle, but normal B-cell changes in the NHL patients were modest. At DL1, 2 DLBCL patients progressed after cycle 2, but one FL patient had stable disease (47% tumor shrinkage, progressing 3 months later after completing maintenance treatment). At DL 2, one DLBCL patient with unrelated pneumonia withdrew after one dose, one DLBCL patient had a partial response (PR, 60% shrinkage, next scan pending), one FL patient progressed after cycle 2, one FL patient achieved a PR (83% shrinkage, continuing now 10 months later), and one CLL patient had an unconfirmed PR during cycle 1 (WBC 84% decreased, progressing after 2 months). At DL3, one patient with SLL progressed after cycle 2 and the other 2 patients with SAEs were not assessed for treatment response. In total, 4/8 (50%) assessable patients (CLL, DLBCL, FL X 2) demonstrated objective evidence of treatment activity.
Conclusion. SQ injections of IMMU-114 appears to avoid the significant administration reactions that has limited the development of other anti-HLA-DR antibodies given IV. With lack of toxicity and preliminary efficacy observed at the two lowest dose levels, DL 2 was declared an acceptable choice for subsequent expansion cohorts. While IMMU-114 demonstrated activity in this population relapsed/refractory to rituximab-containing therapies, the presence of short responses in some patients suggests treatment should be maintained beyond 2 cycles. Thus, the dosing scheme is being amended to allow treatment cycles to be repeated until disease progression, with a goal of determining an appropriate dosing schedule for undertaking a phase II study.

Disclosures
Stephens: Acerta Pharma BV: Research Funding; Immunomedics: Research Funding. Off Label Use: IMMU-114 for treatment of hematologic malignancies. Starodub:Immunomedics: Research Funding. Horne:Immunomedics: Employment. Wegener:Immunomedics: Employment. Goldenberg:Immunomedics, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Stock Options, Patents & Royalties. Christian:Celgene: Consultancy; Seattle Genetics: Consultancy, Research Funding; Acerta: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Immunomedics: Research Funding; Novartis: Other: IDSM.