title: Co-potentiation of antigen recognition: A mechanism to boost weak T cell responses and provide immunotherapy in vivo.
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.
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Michele M
authors.initials: MM
authors.lastname: Hoffmann
authors.affiliation: 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.
authors.forename: Carlos
authors.initials: C
authors.lastname: Molina-Mendiola
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Alfreda D
authors.initials: AD
authors.lastname: Nelson
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Parks
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Edwin E
authors.initials: EE
authors.lastname: Reyes
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hansen
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Govindarajan
authors.initials: G
authors.lastname: Rajagopalan
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Larry R
authors.initials: LR
authors.lastname: Pease
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Adam G
authors.initials: AG
authors.lastname: Schrum
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Gil
keywords: Antigen receptors; Co-potentiation; Immunotherapies; Monovalent Fab fragments; Synergy; T cell antigen recognition; T cell lymphocytes; T cell responses; cancer; melanoma