We have additional potential products for the treatment of cancer and autoimmune diseases, including veltuzumab, our anti-CD20 antibody, and milatuzumab, our anti-CD74 antibody. The latter has received a Department of Defense grant for a clinical study in patients with lupus. Other programs include IMMU-114, a humanized anti-HLA-DR antibody being investigated as a monotherapy for patients with relapsed NHL and CLL.
Veltuzumab is a humanized monoclonal antibody targeting CD20 receptors on B lymphocytes currently under development for the treatment of NHL and autoimmune diseases.
In autoimmune diseases, we are studying the subcutaneous formulation of veltuzumab in patients with immune thrombocytopenia (ITP), in a Phase 1/2 trial. This trial, designed to evaluate different dosing schedules, has completed patient accrual and patients are being followed for up to 5 years. On July 28, 2015 the Office of Orphan Products Development of FDA granted orphan status for the use of veltuzumab for the treatment of ITP.
In oncology, a NCI-funded Phase 1/2 study in patients with aggressive NHL in combination with 90Y-epratuzumab tetraxetan has completed patient enrollment, with patient follow-up continuing.
We are currently evaluating various options for further clinical development of veltuzumab in ITP and other autoimmune disease indications, including pemphigus, as well as in oncology, including licensing arrangements and collaborations with outside study groups.
The Phase I/II trial in adult patients with chronic ITP has completed patient enrollment. For more information on this clinical trial, please go to clinicaltrials.gov.
The National Cancer Institute is funding a Phase I/II study combining veltuzumab with yttrium-90-labeled epratuzumab in patients with relapsed or refractory, aggressive NHL.
Liebman H, Bussel JB, Saleh MN, Horne H, Wegener WA, Goldenberg DM. Comparison of two dosing schedules for subcutaneous injections of low-dose anti-CD20 veltuzumab in relapsed immune thrombocytopenia: final results of a phase I study. Blood 2013; 122(21): 1080.
Liebman HA, Saleh MN, Bussel JB, Negrea OG., Horne H, Wegener WA, Goldenberg, DM. Low-dose anti-CD20 veltuzumab given intravenously or subcutaneously is active in relapsed immune thrombocytopenia: a phase I study. Br J Haematol. 162(5):693-701, Sept 2013.
Tomblyn M, Witzig T, Himelstein A, Kio E, Sharkey RM, Rojo J, Wegener WM, Goldenberg DM. Anti-CD22 radioimmunotherapy (RIT) combined with anti-CD20 immunotherapy in aggressive non-Hodgkin lymphoma (NHL): Phase I results. Proc. Soc. Nucl. Med. 60th Annual Meeting, J. Nucl. Med. 54(Suppl 2): 304P (Abstr. #1368), 2013.
Kalaycio M, Negrea OG, elstrom R, Farber C, Horne H, Wegener WA, Goldenberg DM. Monotherapy with subcutaneous (SC) injections of low doses of humanized anti-CD20 veltuzumab is active in chronic lymphocytic leukemia (CLL). Blood 2012; 120(21): 192.
Negrea GO, Elstrom R, Allen SL, Rai KR, Abbasi RM, Farber CM, Teoh N, Horne H, Wegener WA, Goldenberg DM. Subcutaneous injections of low-dose veltuzumab (humanized anti-CD20 antibody) are safe and active in patients with indolent non-Hodgkin's lymphoma. Haematologica 96(4):567-73, 2011.
Milatuzumab is a humanized monoclonal antibody targeting tumors that express the CD74 antigen, which is present on a variety of hematological tumors and even on some solid cancers, with restricted expression by normal tissues. It has received orphan drug designation from the Food and Drug Administration for the treatment of patients with multiple myeloma or CLL. Milatuzumab is the first anti-CD74 antibody that has entered into human testing and we have completed initial Phase I studies in patients with relapsed multiple myeloma, NHL or CLL.
The anti-CD74 antibody is also being studied subcutaneously in a Phase 1b study in patients with active SLE. The SLE study is supported by a three-year research grant from the Department of Defense with a potential funding of $1.6 million.
Our interest in pursuing milatuzumab in immune diseases is driven by the observations that implicated CD74 in antigen presentation—particularly by dendritic and other immune cells—and as a survival factor for rapidly proliferating malignant cells. Recent findings have determined that CD74 is a receptor for the pro-inflammatory chemokine, macrophage migration-inhibitory factor, and that binding of the factor to CD74 initiates a signaling cascade resulting in proliferation and survival of normal and malignant B cells, such as in CLL. Migration-inhibitory factor is widely expressed by immune cells, particularly macrophages, and is known to play a role in autoimmune disease. Thus, we believe that milatuzumab, by blocking the function of CD74, could be useful in the management of immune diseases either alone or in combination with other agents—including other B-cell antibodies such as epratuzumab and veltuzumab.
This is a Phase Ib study of milatuzumab administered subcutaneously in patients with active SLE funded by a grant from the Department of Defense.
Kaufman JL, Niesvizky R, Stadtmauer EA, Chanan-Khan A, Siegel D, Horne H, Wegener WA, Goldenberg DM. Phase I, multicentre, dose-escalation trial of monotherapy with milatuzumab (humanized anti-CD74 monoclonal antibody) in relapsed or refractory multiple myeloma. Br J Haematol, 163(4): 478-486, 2013.
Chen X, Chang CH, Stein R, Cardillo TM, Gold DV, Goldenberg DM. Prevention of acute graft-versus-host disease in a xenogeneic SCID mouse model by the humanized anti-CD74 antagonistic antibody milatuzumab. Biol Blood Marrow Transplant. 19(1):28-39, Jan 2013.
Frölich D, Blabetafeld D, Reiter K, Giesecke C, Daridon C, Mei HE, Burmester GR, Goldenberg DM, Salama A, Dörner T. The anti-CD74 humanized monoclonal antibody, milatuzumab, which targets the invariant chain of MHC II complexes, alters B-cell proliferation, migration, and adhesion molecule expression. Arthritis Res Ther. 14(2):R54, 2012.
IMMU-114 is a novel humanized antibody directed against an immune response target, HLA-DR, for the treatment of patients with B-cell cancers. HLA-DR is a receptor located on the cell surface whose role is to present foreign objects to the immune system for the purpose of eliciting an immune response. Increased presence of HLA-DR in hematologic cancers has made it a prime target for antibody therapy.
Although other anti-HLA-DR antibodies have been developed, IMMU-114 is distinguished by having a different immunoglobulin class, IgG4, which does not function by the usual effector-cell activities of antibodies, such as complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). As a result, IMMU-114 does not rely on an intact immune system in the patient to kill tumor cells. Furthermore, because ADCC and CDC are believed to play a major role in causing the side effects of antibody therapy, we expect IMMU-114 to be less toxic to patients.
By targeting HLA-DR, a receptor that is different from the antigen targeted by rituximab or other antibodies in development for NHL and other B-cell malignancies, IMMU-114 may represent a new tool in the arsenal to combat these cancers.
The anti-HLA-DR antibody is being investigated in a Phase I dose-escalation study as a monotherapy for patients with NHL or CLL.
Chen X, Chang CH, Stein R, Goldenberg DM. The humanized anti-HLA-DR moAb, IMMU-114, depletes APCs and reduces alloreactive T cells: implications for preventing GVHD. Bone Marrow Transplant. 47(7):967-80, 2012.
Park KH, Sawada T, Murakami T, Ishii Y, Yasuo M, Fuchinoue S, Goldenberg DM, Kubota K. Anti-class II -DR humanized monoclonal antibody, IMMU-114, blocks allogeneic immune response. Am J Surg. 204(4):527-34, 2012.
Stein R, Balkman C, Chen S, Rassnick K, McEntee M, Page R, Goldenberg DM. Evaluation of anti-human leukocyte antigen-DR monoclonal antibody therapy in spontaneous canine lymphoma. Leuk Lymphoma. 2011 Feb;52(2):273-84. doi: 10.3109/10428194.2010.535182. Epub 2010 Dec 6.
Stein R, Gupta P, Chen X, Cardillo TM, Furman RR, Chen S, Chang CH, Goldenberg DM. Therapy of B-cell malignancies by anti-HLA-DR humanized monoclonal antibody, IMMU-114, is mediated through hyperactivation of ERK and JNK MAP kinase signaling pathways. Blood. 2010 Jun 24;115(25):5180-90. doi: 10.1182/blood-2009-06-228288. Epub 2010 Jan 25.
Stein R, Qu Z, Chen S, Solis D, Hansen HJ, Goldenberg DM. Characterization of a humanized IgG4 anti-HLA-DR monoclonal antibody that lacks effector cell functions but retains direct antilymphoma activity and increases the potency of rituximab. Blood. 2006 Oct 15;108(8):2736-44. Epub 2006 Jun 15.