B Cells Desensitization with an Anti-CD79 Antibody: Therapeutic Approach for Autoimmune Diseases Validated In Vivo


NJH ID: #11-15

Background
B lymphocytes play fundamental roles in the pathogenesis of autoimmune disease as well as transplant rejection. Current technologies for treatment of many lymphomas, leukemias, transplant rejection and some autoimmune disorders include monoclonal antibodies (mAb) that target and deplete B cell populations.

Recovery from these treatments requires an extended period of time during which patients are immunosuppressed and therefore susceptible to opportunistic infections.  In addition, this modality does not eliminate all B lineage cells and thus may not be appropriate for all pathologic conditions involving B lymphocytes.
Cluster of Differentiation 79 (CD79) is a transmembrane protein found exclusively in B cells that is the transducer component of B-cell receptor (BCR), generating a signal following recognition of antigen by the BCR. As a consequence CD79 is an ideal candidate molecule for B cell-targeted therapy.
 
Technology
Dr. Cambier and his laboratory discovered that in certain circumstances, subunits of the B cell antigen receptor (BCR) become dissociated rendering the receptor incompetent to transduce activating signals. Based on these observations they produced antibodies against the BCR transducers, CD79a and b, and found that they “desensitize” the BCR and suppress the immune response, autoimmunity, and growth of non-Hodgkin’s B lymphoma. These anti-CD79 mAbs show therapeutic potential to induce reversible inhibition of BCR signaling and B cell function.  This technology exploits the unique qualities of the BCR to reversibly suppress signaling for therapeutic use in autoimmunity, cancer and transplantation. Receptor desensitization and therapeutic efficacy has been demonstrated in vitro and in vivo.
 
Potential Applications

  • Treatment of autoimmune conditions such as rheumatoid arthritis, lupus, and diabetes
  • Treatment of B cell neoplasias
  • Prevention of tissue rejection

 
State of Development
Investigators have shown that administration of an anti-mouse CD79 targeting BCR in a mouse model of lupus, decreased autoantibody production (suppressed B cell responses), decreased skin pathology, and increased survival from 20% to 80%. Furthermore they established that anti-CD79a/b antibodies (intact, or mutants incompetent to bind IgG receptors and activate the complement cascade) block the development of disease and ameliorate ongoing target organ injury in MRL/LPR mouse model of Rheumatoid Arthritis, NOD mice for Type 1 Diabetes and EAE mouse model for MS.

In later experiments they developed a proprietary monoclonal antibody against human CD79 (Curly 14) that has the capacity to desensitize the BCR in vitro.
Further experiments will involve the characterization of the effectiveness of Curly 14 for modulating immune disease, understanding Curly 14 binding affinity, determination of the antibody binding site and the ability to destabilize and/or desensitize B cells in huSCID and human CD79 knockin mouse models.
The creation of a human CD79 expressing mouse model for in-vivo preclinical testing to optimize anti-CD79 therapy is underway. They have successfully produced CD79a and CD79b knockin ES clones, and are currently confirming by doing karyotype analysis.
 
Publications
Vilen et al. 1997. J Immunol. 159(1):231-43.
Vilen et al. 1999. Immunity. 10:239-248.
Li et. al. 2008 J Immunol. 1;181(5):2961-72.
Hardy et.al. 2014 J Immunol192(4):1641-50.

Patent Status
Issued U.S. Patent #6,503,509 and #7,825,224; Issued patents in France, Germany, UK, Australia and New Zealand; Pending in Canada, and Japan
Human CD79 mAb-related patent pending worldwide.

Inventors
John Cambier, Ph.D. and Barbara J. Vilen, Ph.D, Matt Seefeldt, Ph.D. and Ian Hardy, Ph.D.

Licensing Status
This technology is available for licensing.

For Further Information, Contact:
Emmanuel Hilaire, PhD
Manager
Technology Transfer Office
National Jewish Health
1400 Jackson Street, Room M206b
Denver, CO 80206
Voice: 303.398.1262
Fax: 303.270.2352
HilaireE@njhealth.org

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