Background/Purpose

We have previously shown that resistance to Adjuvant Arthritis (AA) is due to the presence of anti-heat shock protein (HSP) antibodies, directed at peptide-6, a 16 amino acid epitope of Mycobacterium Tuberculosis (MT) HSP65. Furthermore, we have shown that polyclonal rat anti-peptide-6 antibodies suppress AA and bind to the whole MT HSP65 molecule as well as its mammalian homolog, HSP60. In this work, we have studied the effect of a humanized anti-peptide-6 monoclonal antibody, termed Prozumab, on various models of autoimmune arthritis and colitis and the mechanism of its anti-inflammatory effect.

Methods

We have recently developed a humanized anti-peptide-6 antibody, termed Prozumab, and evaluated its potential as a therapeutic immunomodulatory drug. We tested its binding to MT HSP65 and mammalian HSP60, its effect on cytokine modulation from human PBMCs, and its therapeutic effects in acute and chronic animal models of arthritis and colitis.

Results

Prozumab bound similarly to recombinant MT HSP65 and mammalian HSP60. Its ability to modulate cytokine balance was established as it induced IL-10 secretion from human PBMC. Moreover, in the presence of Prozumab, a reduction in secretion of IFNg and IL-6 from anti-CD3 activated human PBMC was observed. Administration of this antibody to mice and rats with collagen induced arthritis, adjuvant arthritis and TNBS colitis, induced a change in the cytokine balance and suppression of disease. Treatment with this antibody suppressed disease severity in spontaneous IL-10 knock-out colitis in mice as well. The level of natural anti-peptide-6 antibodies in the serum of patients with rheumatoid arthritis was significantly lower than in healthy controls.

Conclusion

We conclude that HSP65 contains protective B-cell epitopes exposed on its surface, and that natural and acquired resistance to autoimmune arthritis is associated with the ability to develop an antibody response to these epitopes. These antibodies cross react with the human HSP60, modulate cytokine production from human PBMCs and ameliorate disease in experimental autoimmune inflammatory disease models. The high homology between the peptide-6 region in MT HSP65 and the mammalian HSP60 and the similarity of the in vitro binding suggest that HSP60 is its target on mammalian cells. Presence of HSP60 on various mammalian cells has been shown previously. Lower levels of anti-peptide-6 antibodies in patients with RA suggest that they play a role in protection against human autoimmune diseases as well. The monoclonal humanized anti-peptide-6 antibody may serve as a new therapeutic tool for suppression of human arthritis and inflammatory bowel diseases by skewing the immune system selectively towards an anti-inflammatory response.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-humanized-monoclonal-antibody-raised-against-a-heat-shock-protein-epitope-suppresses-autoimmune-inflammatory-diseases-by-skewing-the-immune-system-selectively-towards-an-anti-inflammatory-response/