SBIR-STTR Award

Monoclonal antibody for autoimmune disease Abstract B cells play a major role in the pathogenesis of many autoimmune disorders, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis, and type I diabetes mellitus, as indicated by the efficacy of B cell-targeted therapies like rituximab in thes diseases. Unfortunately, current therapies are predicated on B-cell depletion, which is problematic from a safety standpoint. Due to immunosuppression, existing standard-of-care therapies generate adverse effects, notably opportunistic infections resulting from long-term, severe B cell depletion. Recently, an alternative approach involving the targeting of CD79, the transducer subunit of the B cell receptor (BCR) has been described. Unlike anti-CD20 mAbs, the protective effects of CD79-targeted mAbs do not require cell depletion; rather, they act by inducing an unresponsive or anergic state in which B cells physically relocate and are unavailable to participate in immune response generation. In the murine MRL/lpr model of SLE, anti-CD79 antibodies were potently immunosuppressive and effective at decreasing inflammation and improving survival (Li, 2008). In a collagen-induced arthritis model of rheumatoid arthritis, anti-CD79 antibodies delayed the onset of arthritis and decreased arthritis scores, by inducing anergy with transient, reversible B cell redistribution (Hardy, 2014). Based on these studies, Phase 1 work will identify and characterize a potent anti-CD79 human monoclonal antibody. Unlike other B cell targeted biologics that induce B cell death by ADCC, complement fixation or survival factor starvation-mediated cell death, this approach will induce a transient state of polyclonal B cell anergy. We expect this second generation immunosuppressive therapeutic to be significantly safer than existing B cell targeted antibodies.

Public Health Relevance Statement:


Public Health Relevance:
Autoimmune diseases as a group impose a major health burden. While most autoimmune diseases are individually rare, in the aggregate they affect 5-8% of Americans and can be life-threatening. Current treatments are moderately effective, yet carry a heavy risk of adverse effects. We have identified a monoclonal antibody specific to B cells which shows efficacy in animal models of rheumatoid arthritis and systemic lupus erythematosus. This antibody therapy is safer than competing approaches, because its effects are transient and can be quickly reversed, if necessary. With further development, this antibody will greatly improve the therapeutic options for autoimmune diseases.

Project Terms:
abstracting; Adverse effects; Affect; Affinity; Alternative Therapies; American; anergy; Animal Model; Antibodies; Antibody Therapy; Antigen Receptors; Antigens; Arthritis; Autoimmune Diseases; B-Lymphocytes; base; Binding (Molecular Function); C-terminal; Caring; Cell Death; Cells; Complement; Data; Development; Disease; Drug Kinetics; Generations; Goals; Health; Human; human monoclonal antibodies; Immune response; Immunosuppressive Agents; improved; in vitro Assay; Inflammation; Insulin-Dependent Diabetes Mellitus; Integral Membrane Protein; ITAM; Knock-in Mouse; Life; Lymphocyte antigen; Mediating; Modeling; Monoclonal Antibodies; mouse model; MS4A1 gene; Multiple Sclerosis; Mus; Natural immunosuppression; Opportunistic Infections; Parents; Pathogenesis; peripheral blood; Phase; phase 1 study; Phosphorylation; Play; Population; Primates; protective effect; public health relevance; Receptor Aggregation; Receptors, Antigen, B-Cell; Rheumatoid Arthritis; Risk; rituximab; Role; Safety; sample fixation; Signal Pathway; Signal Transduction; src Homology Region 2 Domain; src-Family Kinases; Starvation; Systemic Lupus Erythematosus; Therapeutic; Time; Toxic effect; Transducers; Tyrosine; Tyrosine Phosphorylation; Work

Monoclonal antibody for autoimmune disease Abstract B cells play a major role in the pathogenesis of many autoimmune disorders, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis, and type I diabetes mellitus (T1D), as indicated by the efficacy of B cell–targeted therapies, e.g. rituximab, in these diseases. Unfortunately, current therapies are predicated on B-cell depletion, which is problematic from a safety standpoint. Due to consequent immunosuppression, existing standard-of-care therapies generate adverse effects, notably opportunistic infections and activation of viruses from latency, due to long-term, severe B cell depletion. Recently, an alternative approach involving the targeting of CD79, the transducer subunit of the B cell receptor (BCR) has been suggested by our group. Unlike anti-CD20 mAbs, the protective effects of CD79-targeted mAbs do not require cell depletion; rather, they act by inducing a reversible unresponsive or anergic state, and thus do not participate in immune response generation. In the murine MRL/lpr model of SLE, anti-CD79 antibodies were potently immunosuppressive and effective at decreasing inflammation and improving survival (Li, 2008). In a collagen-induced arthritis model of rheumatoid arthritis, anti-CD79 antibodies delayed the onset of arthritis and decreased arthritis scores by inducing anergy with transient, reversible B cell redistribution (Hardy, 2014). Based on these studies, Phase 1 work identified and characterized a potent humanized monoclonal anti- human CD79 antibody. The activity of the antibody does not require ADCC, complement fixation, but rather acts by induction of a transient and reversible state of polyclonal B cell anergy. During this Phase II project, we will expand preclinical studies in a transgenic mouse model expressing huCD79 and in a NOD mouse model of T1D. In addition, we will explore the molecular basis of unresponsiveness and analyze toxicity, and pharmacokinetics, as well as activity in non-human primates. We expect this second generation immunosuppressive therapeutic to be significantly safer than existing B cell-targeted antibodies for T1D and potentially other autoimmune diseases.

Public Health Relevance Statement:
Narrative Autoimmune diseases as a group impose a major health burden. While specific autoimmune diseases are infrequent in the population, in the aggregate they affect 5-8% of Americans and can be life-threatening. Current treatments are moderately effective, yet carry a heavy risk of adverse effects. We have identified a monoclonal antibody specific to B cells which shows efficacy in animal models of rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes. This antibody therapy is safer than competing approaches, because its effects are transient and, if necessary, can be quickly reversed. With further development, this antibody will greatly improve the therapeutic options for autoimmune diseases.

Project Terms:
Adverse effects; Affect; Alternative Therapies; American; anergy; Animal Model; Animals; Antibodies; Antibody Response; Antibody Therapy; Arthritis; Autoimmune Diseases; Autoimmunity; B cell therapy; B-Lymphocytes; base; Blocking Antibodies; Cells; Collagen-Induced Arthritis; Complement; curative treatments; Data; desensitization; Development; Disease; Disulfides; Drug Kinetics; Extracellular Domain; Generations; Health; Human; Immune response; Immunosuppressive Agents; improved; In Vitro; in vivo; Inbred NOD Mice; Inflammation; Insulin-Dependent Diabetes Mellitus; Integral Membrane Protein; Knock-in Mouse; latent virus activation; Life; Macaca fascicularis; Mediating; Modeling; Molecular; Monoclonal Antibodies; Monoclonal Antibody CD20; mouse model; Multiple Sclerosis; Mus; Natural immunosuppression; nonhuman primate; Opportunistic Infections; Pathogenesis; Phase; Play; Population; pre-clinical; preclinical study; protective effect; Receptors, Antigen, B-Cell; Reporting; Rheumatoid Arthritis; Risk; risk variant; rituximab; Rodent; Role; Safety; sample fixation; standard of care; Systemic Lupus Erythematosus; Therapeutic; Time; Toxic effect; Transducers; Transgenic Mice; Work