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Human plasma cells engineered to secrete bispecifics drive effective in vivo leukemia killing.
Hill, Tyler F; Narvekar, Parnal; Asher, Gregory D; Edelstein, Jasmine N; Camp, Nathan D; Grimm, Annaiz; Thomas, Kerri R; Leiken, Michael D; Molloy, Katherine M; Cook, Peter J; Arlauckas, Sean P; Morgan, Richard A; Tasian, Sarah K; Rawlings, David J; James, Richard G.
Afiliación
  • Hill TF; University of Washington, Medical Scientist Training Program, Seattle, WA, USA; Seattle Children's Research Institute, Center for Immunity and Immunotherapy, Seattle, WA, USA.
  • Narvekar P; Seattle Children's Research Institute, Center for Immunity and Immunotherapy, Seattle, WA, USA.
  • Asher GD; Seattle Children's Research Institute, Center for Immunity and Immunotherapy, Seattle, WA, USA.
  • Edelstein JN; BE Biopharma, Cambridge, MA, USA.
  • Camp ND; Seattle Children's Research Institute, Center for Immunity and Immunotherapy, Seattle, WA, USA.
  • Grimm A; Seattle Children's Research Institute, Center for Immunity and Immunotherapy, Seattle, WA, USA.
  • Thomas KR; Seattle Children's Research Institute, Center for Immunity and Immunotherapy, Seattle, WA, USA.
  • Leiken MD; BE Biopharma, Cambridge, MA, USA.
  • Molloy KM; BE Biopharma, Cambridge, MA, USA.
  • Cook PJ; Seattle Children's Research Institute, Center for Immunity and Immunotherapy, Seattle, WA, USA.
  • Arlauckas SP; BE Biopharma, Cambridge, MA, USA.
  • Morgan RA; BE Biopharma, Cambridge, MA, USA.
  • Tasian SK; Children's Hospital of Philadelphia, Division of Oncology and Center for Childhood Cancer Research, Philadelphia, PA, USA; Department of Pediatrics and Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  • Rawlings DJ; Seattle Children's Research Institute, Center for Immunity and Immunotherapy, Seattle, WA, USA; University of Washington, Departments of Pediatrics and Immunology, Seattle, WA, USA.
  • James RG; Seattle Children's Research Institute, Center for Immunity and Immunotherapy, Seattle, WA, USA; University of Washington, Departments of Pediatrics and Pharmacology, Seattle, WA, USA. Electronic address: richard.james@seattlechildrens.org.
Mol Ther ; 32(8): 2676-2691, 2024 Aug 07.
Article en En | MEDLINE | ID: mdl-38959896
ABSTRACT
Bispecific antibodies are an important tool for the management and treatment of acute leukemias. As a next step toward clinical translation of engineered plasma cells, we describe approaches for secretion of bispecific antibodies by human plasma cells. We show that human plasma cells expressing either fragment crystallizable domain-deficient anti-CD19 × anti-CD3 (blinatumomab) or anti-CD33 × anti-CD3 bispecific antibodies mediate T cell activation and direct T cell killing of B acute lymphoblastic leukemia or acute myeloid leukemia cell lines in vitro. We demonstrate that knockout of the self-expressed antigen, CD19, boosts anti-CD19-bispecific secretion by plasma cells and prevents self-targeting. Plasma cells secreting anti-CD19-bispecific antibodies elicited in vivo control of acute lymphoblastic leukemia patient-derived xenografts in immunodeficient mice co-engrafted with autologous T cells. In these studies, we found that leukemic control elicited by engineered plasma cells was similar to CD19-targeted chimeric antigen receptor-expressing T cells. Finally, the steady-state concentration of anti-CD19 bispecifics in serum 1 month after cell delivery and tumor eradication was comparable with that observed in patients treated with a steady-state infusion of blinatumomab. These findings support further development of ePCs for use as a durable delivery system for the treatment of acute leukemias, and potentially other cancers.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Plasmáticas / Anticuerpos Biespecíficos / Antígenos CD19 / Ensayos Antitumor por Modelo de Xenoinjerto Límite: Animals / Humans Idioma: En Revista: Mol Ther Asunto de la revista: BIOLOGIA MOLECULAR / TERAPEUTICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Plasmáticas / Anticuerpos Biespecíficos / Antígenos CD19 / Ensayos Antitumor por Modelo de Xenoinjerto Límite: Animals / Humans Idioma: En Revista: Mol Ther Asunto de la revista: BIOLOGIA MOLECULAR / TERAPEUTICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos