Lee J, Lundgren DK, Mao X, Manfredo-Vieira S, Nunez-Cruz S, Williams EF, Assenmacher CA, Radaelli E, Oh S, Wang B, Ellebrecht CT, Fraietta JA, Milone MC, Payne AS: Antigen specific B-cell depletion for precision therapy of mucosal pemphigus vulgaris. J. Clin. Invest., In-Press Preview, 2020. As an antigen-specific precision cellular immunotherapy for autoimmunity has not previously advanced to human clinical trials, there has been no direct precedent for the appropriate preclinical development path. Following discussions with FDA, Jinmin, Daniel and Xuming collaborated with others in the Payne and Milone labs and throughout the University of Pennsylvania to perform the definitive preclinical studies that supported the DSG3-CAART Investigational New Drug application, which was cleared by the FDA in September 2019 and enabled a first-in-human trial of this precision immunotherapy. We hope the scope of experiments presented in this manuscript may serve as a valuable reference for investigators developing novel cellular immunotherapies for autoimmune disease indications.
Tovanabutra N, Payne AS: Clinical outcomes and safety of rituximab for pemphigoid diseases. J. Amer. Acad. Dermatol.,82:1237-1239, 2020, with accompanying supplemental Mendeley dataset) Napatra's retrospective analysis of 38 pemphigoid patients indicates that rituximab is an effective steroid-sparing therapy in pemphigoid, resulting in approximately 75% reduction in median daily prednisone dosage, and complete remission (CR) of disease symptoms on minimal therapy in 76% of patients (including CR off steroids in 39% of patients). Median time to disease relapse was 6.2 months. No differences in efficacy were observed between rheumatoid arthritis and lymphoma dose regimens. These data help to frame expectations of providers and patients when selecting steroid-sparing therapy for pemphigoid.
Kushner CJ, Wang S, Tovanabutra N, Tsai DE, Werth VP, Payne AS: Factors associated with complete remission after rituximab therapy for pemphigus. JAMA Dermatol., 155:1404-1409, 2019. Carolyn and Napatra's paper uses multivariate regression analysis of clinical outcomes data from the Penn Autoimmune Blistering Clinic, which encompasses one of the largest cohorts of pemphigus patients treated with rituximab. Their analysis indicates that older age and use of a lymphoma dose regimen is associated with higher odds of complete remission after rituximab therapy for pemphigus, whereas higher body mass index is associated with lower rates of complete remission.
Ellebrecht CT, Lundgren DK, Payne AS: On the mark: genetically engineered immunotherapies for autoimmunity.Curr. Opin. Immunol., 61:69-73, 2019. Christoph and Daniel's review highlights novel cellular immunotherapy strategies for antigen-specific targeting of autoreactive B and T cell populations.
Ellebrecht CT*, Mukherjee EM*, Zheng Q, Choi EJ, Reddy SG, Mao X, Payne AS:Autoreactive IgG and IgA B cells evolve through distinct subclass switch pathways in the autoimmune disease pemphigus vulgaris.Cell Reports, 24:2370-2380, 2018.*contributed equally Christoph and Eric use subclass-specific deep sequencing paired with antigen-specific B cell repertoire cloning to describe the lineage relationships between desmoglein-specific IgG1, IgG4, IgA1, and IgA2 in pemphigus vulgaris. They found that autoreactive IgG4 B cell clones are largely clonally distinct from the more clonally inter-related IgG1-IgA1-IgA2 axis in PV and that IgG4 most often recognized pathogenic domains within desmoglein 3, whereas other subclasses recognized a broader range of epitopes. They also performed an in-depth analysis of the reproducibility between technical and biological replicates from primary human blood samples. Eric wrote a blogpost for Science Trends describing the work - check it out!
Lee J, Payne AS: Advances in targeting CAR-T therapy for immune-mediated diseases. Cell and Gene Therapy Insights, 4(4), 255-265, 2018. Jinmin's review covers the latest advancements in applications of chimeric immunoreceptor technology to achieve antigen-specific cytotoxic and regulatory T cell control of autoimmune and alloimmune diseases.
Spindler V, Eming R, Schmidt E, Amagai M, Grando S, Jonkman MF, Kowalczyk AP, Muller EJ, Payne AS, Pincelli C, Sinha AA, Sprecher E, Zillikens D, Hertl M, Waschke J:Mechanisms causing loss of keratinocyte cohesion in pemphigus.J.Invest.Dermatol., 138:32-37, 2018. A consensus document on the mechanisms of cellular pathophysiology of pemphigus, published after the Pathogenesis of Pemphigus and Pemphigoid meeting in Munich Germany in 2016.
Mao X, Cho MJ, Ellebrecht CT, Mukherjee EM, Payne AS: Stat3 regulates desmoglein 3 transcription in epithelial keratinocytes. JCI Insight 2(9): e92253, 2017. Xuming's paper was the first to identify a transcription factor that regulates desmoglein 3 expression, which explains the mechanism for how steroids work quickly to improve disease in pemphigus and affords new insight into the physiologic control of desmoglein 3 expression in epidermis, as well as the clinical significance of its dysregulation in head and neck squamous cell cancers and other epithelial carcinomas.
Ran NA, Payne AS: Rituximab therapy in pemphigus and other autoantibody-mediated diseases.F1000 Research 6:83, 2017. Nina's review analyzes the published data on the efficacy of rituximab in pemphigus and other select autoantibody-mediated diseases.
Ellebrecht CT, Payne AS: Setting the target for pemphigus vulgaris therapy. JCI Insight 2(5): e92021, 2017. Christoph's review highlights past and recent strategies for antigen-specific therapy of pemphigus.
Chen J, Zheng Q, Hammers CM, Ellebrecht CT, Mukherjee EM, Tang HY, Lin C, Yuan H, Pan M, Langenhan J, Komorowski L, Siegel DL, Payne AS, Stanley JR: Proteomic analysis of pemphigus autoantibodies indicates a larger, more diverse, and more dynamic repertoire than determined by B cell genetics. Cell Reports 18(1): 237-247, 2017. This collaborative effort with the Stanley lab was the first to report the large-scale proteomic analysis of serum antibodies in a model autoimmune disease, pemphigus vulgaris.
Ellebrecht CT, Bhoj VG, Nace A, Choi EJ, Mao X, Cho MJ, Di Zenzo G, Lanzavecchia A, Seykora JT, Cotsarelis G, Milone MC, Payne AS: Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 353: 179-184, 2016. Christoph's paper describes the preclinical development of a novel strategy for the targeted cellular immunotherapy of pemphigus vulgaris using chimeric autoantibody receptor (CAAR) T cells, which achieve antigen-specific B cell depletion by directing T cell cytotoxicity against B cells expressing an anti-desmoglein 3 B cell receptor. Featured in commentaries: Leslie, M. (2016), Science, 353:14; Amagai, M. (2016), New Engl. J. Med., 375:1487-1489; Galy A. (2016), Mol. Ther., 13:1339-1341; Chatenoud, L. (2016), Nat. Biotech., 34:930-932.
Cho MJ, Ellebrecht CT, Hammers CM, Mukherjee EM, Sapparapu G, Boudreaux CE, McDonald SM, Crowe JE, Jr., Payne AS.: Determinants of VH1-46 cross-reactivity to pemphigus vulgaris autoantigen desmoglein 3 and rotavirus antigen VP6. J. Immunol. 197(4): 1065-73, 2016. Michael's paper was inspired by the intriguing finding that VH1-46 antibody gene usage has been associated with autoreactivity to the self-antigen desmoglein 3 in pemphigus vulgaris, as well as anti-viral reactivity to the rotavirus VP6 coat protein. He showed that cross-reactivity to desmoglein 3 and VP6 is enriched in VH1-46 B cells and that cross-reactive VH1-46 monoclonal antibodies can be identified that both cause suprabasal blisters in human skin and protect from rotavirus infection. However, such cross-reactivity is rare due to the differing nature of mutations that confer desmoglein 3 versus VP6 reactivity, which limits the onset of pemphigus autoimmunity.
Cho MJ, Ellebrecht CT, Payne AS: The dual nature of interleukin 10 in pemphigus vulgaris. Cytokine, 73:335-41, 2015. Michael's review assesses the role of interleukin 10 in pemphigus pathogenesis. Interleukin 10 induces protective responses through regulatory B and T cells, while at the same time promoting class switch to IgG4, the hallmark of the pathogenic antibody population in pemphigus.
Hammers CM, Chen J, Lin C, Kacir S, Siegel DL, Payne AS, Stanley JR: Persistence of anti-desmoglein 3 IgG+ B-cell clones in pemphigus patients over years.J. Invest. Dermatol., 135:742-9, 2015. In this collaborative effort with the Stanley lab, Christoph Hammers showed that the identical anti-desmoglein 3 B cell clones are identified during active disease and after disease relapse, whereas no anti-desmoglein 3 B cells are found in patients in long-term remission, suggesting that disease relapse in pemphigus is caused by incomplete B cell depletion rather than the generation of new non-tolerant B cell clones.
Cho MJ, Lo ASY, Mao X, Nagler AR, Ellebrecht CT, Mukherjee EM, Hammers CM, Choi EJ, Sharma PM, Uduman M, Li H, Rux AH, Farber SA, Rubin CB, Kleinstein SH, Sachais BS, Posner MR, Cavacini LA, Payne AS: Shared VH1-46 gene usage by pemphigus vulgaris autoantibodies indicates common humoral immune responses among patients. Nature Commun. 5: 4167, 2014. Michael's paper identified that the VH1-46 gene is commonly used by anti-desmoglein 3 B cells in pemphigus vulgaris patients and defined amino acid residues in VH1-46 antibodies that are necessary and sufficient to confer desmoglein 3 reactivity. Collectively these experiments suggest that VH1-46 gene usage is common in pemphigus vulgaris because VH1-46 B cells require few to no somatic mutations to bind desmoglein 3, which favors their early selection in the immune response. Common VH gene usage among patients indicates common mechanisms for developing autoimmunity in pemphigus vulgaris.
Ellebrecht CT, Choi EJ, Allman DM, Tsai DE, Wegener WA, Goldenberg DM, Payne AS: Subcutaneous veltuzumab, a humanized anti-CD20 antibody, for treatment of refractory pemphigus vulgaris. JAMA Dermatol. 150: 1331-1335, 2014. This study describes the successful treatment of a pemphigus vulgaris patient with veltuzumab, a novel anti-CD20 monoclonal antibody administered by subcutaneous injection under a compassionate use investigational new drug application.
Mao X, Li H, Sano Y, Gaestel M, Park JM, Payne AS: MAPKAP kinase 2 (MK2)-dependent and independent models of blister formation in pemphigus vulgaris.J. Invest. Dermatol. 134: 68-76, 2014. Xuming's work builds upon his past publications showing that pathogenic anti-desmoglein 3 antibodies cause endocytosis and degradation of newly synthesized desmoglein 3, whereas nonpathogenic antibodies do not affect desmoglein 3 incorporation into the desmosome. He subsequently showed that p38 MAPK activation is not required for the initial loss of cell adhesion in pemphigus vulgaris, but augments blistering by inducing desmoglein 3 endocytosis. Although p38 MAPK inhibitors could improve disease in pemphigus, they are toxic. In this paper, Xuming identified that inhibition of MK2, a downstream effector of p38, similarly blocks pemphigus autoantibody-induced endocytosis of desmoglein 3 and ameliorates spontaneous skin blistering, thus identifying a valuable adjunctive therapy for pemphigus vulgaris. Featured in commentary: Galichet et al (2014), J. Invest. Dermatol., 134:8-10.
Funakoshi T, Lunardon L, Ellebrecht CT, Nagler AR, O’Leary CE, Payne AS: Enrichment of total serum IgG4 in pemphigus patients. Br.J.Dermatol. 167: 1245-1253, 2012. Takeru's and Luisa's paper showed that total serum IgG4 is enriched in pemphigus patients and that desmoglein-reactive antibodies comprise roughly 7% of total IgG4 in pemphigus vulgaris patients. These studies indicate that the switch of autoreactive B cells to the IgG4 subclass is sufficient to elevate total serum IgG4 in many pemphigus patients.
Lunardon L, Payne AS: Inhibitory human anti-chimeric antibodies to rituximab in a pemphigus patient.J. Allerg. Clin. Immunol.,130(3):800-803, 2012. Luisa's report described neutralizing human anti-chimeric antibodies (HACA) to rituximab in a pemphigus vulgaris patient who experienced infusion reactions and lack of treatment effect. According to the rituximab prescribing information, anti-drug antibodies are observed in 56% of pemphigus vulgaris patients receiving rituximab therapy, although the clinical significance of this immunogenicity is currently unclear.
*Picture courtesy of Emily Petersen, Science
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