Publications

For a complete list of publications, click here.

Featured:

Lee CS*, Chen S*, Berry CT, Kelly AR, Herman PJ, Oh S, O’Connor RS, Payne AS†, Ellebrecht CT†. Fate induction in CD8 chimeric antigen receptor T cells through asymmetric cell division. Nature, 2024. *contributed equally, †co-corresponding

Casey and Sisi performed a tour-de-force study led by Christoph Ellebrecht describing asymmetric cell division in CAR T cells (CARTs) after target cell lysis. They showed that asymmetry in the inheritance of RNA transcripts as well as surface proteomes led to differences in cell fate, with proximal daughter cells as activated effector CARTs, and distal daughter cells adopting a memory CART fate. We believe that distal daughter CARTs are an ideal CART therapeutic subset, superior to traditional methods of selection for memory markers such as CD62L, which could be up- or down-regulating at the time of CART selection and hence could lead to products with more heterogeneous fates.

Anderson E, Powell M, Yang E, Kar A, Leung TM, Sison C, Steinberg R, Mims R, Choudhury A, Espinosa C, Zelmanovich J, Okoye NC, Choi EJ, Marder G, Narain. S, Gregersen PK, Mackay M, Diamond B, Levy T, Zanos TP, Khosroshahi A, Sanz I, Luning Prak ET, Bar-Or A, Merrill J, Arriens C, Pardo G, Guthridge J, James J, Payne A, Utz PJ, Boss JM, Aranow C, Davidson A: Factors associated with immune responses to SARS-CoV-2 vaccination in autoimmune disease individuals. JCI Insight, 2024.

Eun and I were delighted to collaborate with Amit Bar-Or, Nina Luning Prak, and the nationwide Autoimmunity Centers of Excellence to enroll and analyze the NIAID ACV02 study of COVID-19 vaccine responses in autoimmune disease individuals. This study provided real world data on how COVID-19 vaccine responses among autoimmune disease individuals were affected by immunosuppressive therapies and the safety of vaccination in this patient population.

Pham MC, Masi G, Patzina R, Obaid AH, Oxendine SR, Oh S, Payne AS, Nowak RJ, O’Connor KC: Individual myasthenia gravis autoantibody clones can efficiently mediate multiple mechanisms of pathology. Acta Neuropathol., 2023.

Sangwook continued his collaboration with Minh in the O’Connor laboratory to help study mechanisms of autoimmunity in myasthenia gravis caused by autoantibodies against the acetylcholine receptor (AChR).  They found that anti-AChR antibodies were often multi-functional, mediating pathology through a combination of complement activation, receptor blockade, and/or antigenic modulation.

Oh S, Mao X, Manfredo-Vieira S, Lee J, Patel D, Choi EJ, Alvarado A, Cottman-Thomas E, Maseda D, Tsao PY, Ellebrecht CT, Khella SL, Richman DP, O’Connor KC, Herzberg U, Binder GK, Milone MC, Basu S, Payne AS: Precision targeting of autoantigen-specific B-cells in muscle-specific tyrosine kinase myasthenia gravis with chimeric autoantibody receptor T-cells. Nature Biotechnol., 2023.

Sangwook worked with Xuming, Silvio, and collaborators throughout Penn, Yale, UC-Davis, and Cabaletta Bio to bring our second CAART therapy, MuSK-CAART for MuSK myasthenia gravis, to human clinical trials. We are grateful for the opportunity to learn from our neurology colleagues Kevin O’Connor, David Richman, Sami Khella, and others about the similarities and differences between MuSK myasthenia gravis and mucosal pemphigus vulgaris as we developed precision cellular immunotherapies for both diseases.  Silvio wrote a blogpost describing the work for the Nature Bioengineering Community.

Fichtner ML, Hoehn KB, Ford EE, Mane-Damas M, Oh S, Waters P, Payne AS, Smith ML, Watson, CT, Losen M, Martinez-Martinez P, Nowak RJ, Kleinstein SH, O’Connor KC: Reemergence of pathogenic, autoantibody-producing B cell clones in myasthenia gravis following B cell depletion therapy. Acta Neuropathol. Commun., 2022.

We are honored to have worked with Miriam in Kevin O’Connor’s laboratory at Yale to assist her studies on B cell profiling of MuSK myasthenia gravis patients before and after B cell depletion therapy.  They identified clonal variants in MuSK myasthenia gravis patients that survived B cell depletion therapy and re-emerged prior to disease relapse. In addition, pathogenic MuSK Ig1-domain targeting antibodies were identified that disrupted acetylcholine receptor clustering, expanding the repertoire of anti-MuSK monoclonal antibodies available for study.

Tovanabutra N, Bax CE, Feng R, Kushner CJ, Payne AS: Temporal outcomes after rituximab therapy for pemphigus vulgaris. J. Invest. Dermatol., 2022.

Napatra and Christina’s retrospective study to describe the clinical and serologic outcomes from a historical cohort of pemphigus vulgaris patients was motivated by our desire to understand timeframes for disease remission and relapse after rituximab therapy, which can inform clinical trial design. Our study outcomes closely matched the 12-month rate of complete remission off steroids in a prospective randomized clinical trial of rituximab and corticosteroids in pemphigus (Werth et al, NEJM 2021), supporting the utility of the dataset. In addition, we explored the utility of the DSG3 ELISA as a biomarker for future achievement of complete remission off steroids and identified cutoff values with high sensitivity or specificity for this endpoint. The detailed graphs included in the supplemental data serve as a historical control dataset that will help investigators planning clinical trials in pemphigus vulgaris and may also inform physician and patient expectations after rituximab therapy for pemphigus vulgaris.

Ellebrecht CT, Maseda D, Payne AS: Pemphigus and Pemphigoid: From Disease Mechanisms to Druggable Pathways. J. Invest. Dermatol., 2021.

In this JID Autoimmunity Issue, Christoph describes the latest understanding of the pathophysiology of pemphigus and pemphigoid and what disease pathways are currently being targeted in clinical trials. Thanks to Damian for the expert illustrations!

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., 130:6317-6324, 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 and the Payne lab team of Daniel, Xuming, Silvio, Sangwook, and Baomei collaborated with labs throughout the University of Pennsylvania and at Cabaletta Bio 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.

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.

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!

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.

Kasperkiewicz M, Ellebrecht CT, Takahashi H, Yamagami J, Zillikens D, Payne AS, Amagai M: Pemphigus. Nature Reviews Disease Primers 11(3): 17026, 2017.

A relatively comprehensive overview of disease epidemiology, pathophysiology, diagnosis, treatment, prognosis, and quality of life. Check out the graphical summary online!

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.

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