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Hoffmann MM, Molina-Mendiola C, Nelson AD, et al. Co-potentiation of antigen recognition: A mechanism to boost weak T cell responses and provide immunotherapy in vivo. Sci Adv. 2015;1(9):e1500415doi: 10.1126/sciadv.1500415.
Hoffmann, M. M., Molina-Mendiola, C., Nelson, A. D., Parks, C. A., Reyes, E. E., Hansen, M. J., Rajagopalan, G., Pease, L. R., Schrum, A. G., & Gil, D. (2015). Co-potentiation of antigen recognition: A mechanism to boost weak T cell responses and provide immunotherapy in vivo. Science advances, 1(9), e1500415. https://doi.org/10.1126/sciadv.1500415
Hoffmann, Michele M, et al. "Co-potentiation of antigen recognition: A mechanism to boost weak T cell responses and provide immunotherapy in vivo." Science advances vol. 1,9 (2015): e1500415. doi: https://doi.org/10.1126/sciadv.1500415
Hoffmann MM, Molina-Mendiola C, Nelson AD, Parks CA, Reyes EE, Hansen MJ, Rajagopalan G, Pease LR, Schrum AG, Gil D. Co-potentiation of antigen recognition: A mechanism to boost weak T cell responses and provide immunotherapy in vivo. Sci Adv. 2015 Oct 02;1(9):e1500415. doi: 10.1126/sciadv.1500415. eCollection 2015 Oct. PMID: 26601285; PMCID: PMC4646799.
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Sci Adv. 2015 Oct 02;1(9):e1500415. doi: 10.1126/sciadv.1500415. eCollection 2015 Oct.

Co-potentiation of antigen recognition: A mechanism to boost weak T cell responses and provide immunotherapy in vivo.

Science advances

Michele M Hoffmann, Carlos Molina-Mendiola, Alfreda D Nelson, Christopher A Parks, Edwin E Reyes, Michael J Hansen, Govindarajan Rajagopalan, Larry R Pease, Adam G Schrum, Diana Gil

Affiliations

  1. Department of Immunology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
  2. Department of Immunology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. ; Department of Statistics, Polytechnic University of Catalonia, Barcelona 08034, Spain.

PMID: 26601285 PMCID: PMC4646799 DOI: 10.1126/sciadv.1500415

Abstract

Adaptive immunity is mediated by antigen receptors that can induce weak or strong immune responses depending on the nature of the antigen that is bound. In T lymphocytes, antigen recognition triggers signal transduction by clustering T cell receptor (TCR)/CD3 multiprotein complexes. In addition, it hypothesized that biophysical changes induced in TCR/CD3 that accompany receptor engagement may contribute to signal intensity. Nonclustering monovalent TCR/CD3 engagement is functionally inert despite the fact that it may induce changes in conformational arrangement or in the flexibility of receptor subunits. We report that the intrinsically inert monovalent engagement of TCR/CD3 can specifically enhance physiologic T cell responses to weak antigens in vitro and in vivo without stimulating antigen-unengaged T cells and without interrupting T cell responses to strong antigens, an effect that we term as "co-potentiation." We identified Mono-7D6-Fab, which biophysically altered TCR/CD3 when bound and functionally enhanced immune reactivity to several weak antigens in vitro, including a gp100-derived peptide associated with melanoma. In vivo, Mono-7D6-Fab induced T cell antigen-dependent therapeutic responses against melanoma lung metastases, an effect that synergized with other anti-melanoma immunotherapies to significantly improve outcome and survival. We conclude that Mono-7D6-Fab directly co-potentiated TCR/CD3 engagement by weak antigens and that such concept can be translated into an immunotherapeutic design. The co-potentiation principle may be applicable to other receptors that could be regulated by otherwise inert compounds whose latent potency is only invoked in concert with specific physiologic ligands.

Keywords: Antigen receptors; Co-potentiation; Immunotherapies; Monovalent Fab fragments; Synergy; T cell antigen recognition; T cell lymphocytes; T cell responses; cancer; melanoma

References

  1. Proc Natl Acad Sci U S A. 2015 Feb 3;112(5):1517-22 - PubMed
  2. Immunity. 2006 Feb;24(2):133-9 - PubMed
  3. Cell. 2008 Nov 14;135(4):702-13 - PubMed
  4. Immunity. 2009 Jun 19;30(6):777-88 - PubMed
  5. Cell. 2002 Jun 28;109(7):901-12 - PubMed
  6. Cancer Res. 1976 Sep;36(9 pt.1):3160-5 - PubMed
  7. J Biol Chem. 2009 Nov 6;284(45):31028-37 - PubMed
  8. J Immunol. 2008 Jul 1;181(1):243-55 - PubMed
  9. J Immunol. 1988 Feb 15;140(4):1081-8 - PubMed
  10. PLoS Biol. 2009 Dec;7(12):e1000253 - PubMed
  11. Nat Rev Drug Discov. 2013 Feb;12(2):130-46 - PubMed
  12. Immunity. 2007 Jan;26(1):43-54 - PubMed
  13. Oncoimmunology. 2013 Jun 1;2(6):e23972 - PubMed
  14. Curr Protoc Immunol. 2001 May;Chapter 20:Unit 20.1 - PubMed
  15. J Immunol. 2006 Feb 1;176(3):1498-505 - PubMed
  16. J Immunol. 2012 Aug 15;189(4):2054-62 - PubMed
  17. Nat Immunol. 2014 Sep;15(9):875-83 - PubMed
  18. J Immunol. 2015 Feb 1;194(3):950-9 - PubMed
  19. Cancer Res. 2011 Aug 15;71(16):5455-66 - PubMed
  20. N Engl J Med. 2010 Aug 19;363(8):711-23 - PubMed
  21. J Exp Med. 2005 Feb 21;201(4):517-22 - PubMed
  22. J Immunol. 2011 Feb 15;186(4):2282-90 - PubMed
  23. Immunol Today. 1995 May;16(5):223-5 - PubMed
  24. Proc Natl Acad Sci U S A. 1989 May;86(9):3311-5 - PubMed
  25. Structure. 2002 Nov;10(11):1521-32 - PubMed
  26. J Exp Med. 1998 Jul 20;188(2):277-86 - PubMed
  27. Mol Cell. 2003 Dec;12(6):1367-78 - PubMed
  28. Cell. 2001 Jun 29;105(7):913-23 - PubMed
  29. Int Immunol. 1998 Dec;10(12):1777-88 - PubMed
  30. PLoS One. 2008 Mar 05;3(3):e1747 - PubMed
  31. J Exp Med. 2003 Aug 18;198(4):569-80 - PubMed
  32. J Immunol. 2008 Mar 15;180(6):3900-9 - PubMed
  33. J Biol Chem. 2012 Dec 14;287(51):42936-50 - PubMed
  34. Blood. 2005 Jul 15;106(2):601-8 - PubMed
  35. Eur J Immunol. 1990 Mar;20(3):707-10 - PubMed
  36. Biores Open Access. 2013 Jun;2(3):222-6 - PubMed
  37. Nat Rev Immunol. 2011 Jan;11(1):47-55 - PubMed
  38. J Virol. 1999 May;73(5):3702-8 - PubMed
  39. J Immunol. 2012 Jun 15;188(12):5819-23 - PubMed
  40. J Immunol. 2010 Sep 1;185(5):2951-9 - PubMed
  41. Immunity. 1998 Oct;9(4):459-66 - PubMed
  42. Immunol Rev. 2003 Feb;191:38-46 - PubMed
  43. Cold Spring Harb Symp Quant Biol. 1989;54 Pt 2:657-66 - PubMed
  44. Eur J Immunol. 1991 Jul;21(7):1703-9 - PubMed

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