NJH ID: #09-17
Background
Type 1 diabetes (T1D) is an increasingly common, incurable autoimmune disease. It is estimated that about 80,000 children develop the disease each year. The risk of developing T1D is genetically closely-linked in mice, rats and humans to structurally similar MHCII alleles with similar peptide-binding properties. In the non obese diabetic (NOD) mouse model of T1D, the crucial MHCII allele is called, IAg7. Although during the course of T1D in NOD mice CD4 T cells appear in the pancreas specific for IAg7, it is the T cell response to a particular insulin derived peptide (B:9-23) presented by IAg7 that is required for development of the disease. Recent studies by investigators at National Jewish Health (NJH) have unequivocally identified the correct register (register 3) of B:9-23 binding to IAg7 for the vast majority of pathogenic T cells. This binding register had been overlooked in previous studies, because of very weak B:9-23 binding compared to other registers.
Technology
Dr. John Kappler’s group at NJH have re-engineered the B:9-23 peptide to bind very strongly to IAg7 in register 3. Using recombinant IAg7/B:9-23 register 3 complexes, they have generated two inhibitorymonoclonal antibodies, 287 and 4D12, directed at the B:9-23 peptide in register 3 to block diabetogenic T cells interaction. These i antibodies will block the interaction between MHC and the pathogenic T cells involved in the initiation/progression of T1D.
Potential Applications
These engineered two IAg7/B:9-23 complexes are unique tools for both diagnosis and preventive treatment of T1D.
State of Development
Tetramer-positive T-cell clones isolated from T1D patients that responded to stimulation by B:11-23 peptide and denatured insulin protein were conclusively shown to recognize B:11-23 bound to HLA-DQ8 in the low-affinity register 3. Recently our structural studies showed the B:11-23 is bound to HLA-DQ8 in the fashion as B:11-23 bound to MHC in NOD mice.
Publications
Nakayama M et al. Proc Natl Acad Sci U S A. 2015 Apr 7;112(14):4429-34, 2015 PMID: 25831495
Yang J et al. Proc Natl Acad Sci U S A. 2015 2014 Oct 14;111(41):14840-5. PMID: 25267644
Zhang L, et al. Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):2656-61, 2014 PMID: 24550292
- Crawford F, et al. Proc Natl Acad Sci U S A. 108:16729-34, 2011. PMC3189014. PMID: 21949373
Stadinski BD, et al. Proc. Natl. Acad. Sci. USA 107: 10978-10983, 2010. PMC 2890771. PMID: 20534455
Stadinski BD, et al. Nat. Immunol. 11: 225-231, 2010. PMC 3166626. PMID: 20139986
Patent Status
- US #8,673,300. Other US and international pending.
Inventors
John Kappler, PhD, Brian Stadinski, PhD, Li Zhang, PhD, and George Eisenbarth, MD
Licensing Status
This technology is available for licensing
For Further Information, Contact:
Emmanuel Hilaire, PhD
Director
Technology Transfer Office
National Jewish Health
1400 Jackson St., Room M206b
Denver, CO 80206
Voice: 303.398.1262
Fax: 303.270.2352
HilaireE@njhealth.org
