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Exosome Surface Display of IL12 Results in Tumor-Retained Pharmacology with Superior Potency and Limited Systemic Exposure Compared with Recombinant IL12.
Lewis, Nuruddeen D; Sia, Chang Ling; Kirwin, Katherine; Haupt, Sonya; Mahimkar, Gauri; Zi, Tong; Xu, Ke; Dooley, Kevin; Jang, Su Chul; Choi, Bryan; Boutin, Adam; Grube, Andrew; McCoy, Christine; Sanchez-Salazar, Jorge; Doherty, Michael; Gaidukov, Leonid; Estes, Scott; Economides, Kyriakos D; Williams, Douglas E; Sathyanarayanan, Sriram.
Afiliación
  • Lewis ND; Codiak BioSciences Inc., Cambridge, Massachusetts.
  • Sia CL; Codiak BioSciences Inc., Cambridge, Massachusetts.
  • Kirwin K; Codiak BioSciences Inc., Cambridge, Massachusetts.
  • Haupt S; Codiak BioSciences Inc., Cambridge, Massachusetts.
  • Mahimkar G; Codiak BioSciences Inc., Cambridge, Massachusetts.
  • Zi T; Codiak BioSciences Inc., Cambridge, Massachusetts.
  • Xu K; Codiak BioSciences Inc., Cambridge, Massachusetts.
  • Dooley K; Codiak BioSciences Inc., Cambridge, Massachusetts.
  • Jang SC; Codiak BioSciences Inc., Cambridge, Massachusetts.
  • Choi B; Codiak BioSciences Inc., Cambridge, Massachusetts.
  • Boutin A; Codiak BioSciences Inc., Cambridge, Massachusetts.
  • Grube A; Codiak BioSciences Inc., Cambridge, Massachusetts.
  • McCoy C; Codiak BioSciences Inc., Cambridge, Massachusetts.
  • Sanchez-Salazar J; Codiak BioSciences Inc., Cambridge, Massachusetts.
  • Doherty M; Codiak BioSciences Inc., Cambridge, Massachusetts.
  • Gaidukov L; Codiak BioSciences Inc., Cambridge, Massachusetts.
  • Estes S; Codiak BioSciences Inc., Cambridge, Massachusetts.
  • Economides KD; Codiak BioSciences Inc., Cambridge, Massachusetts.
  • Williams DE; Codiak BioSciences Inc., Cambridge, Massachusetts.
  • Sathyanarayanan S; Codiak BioSciences Inc., Cambridge, Massachusetts. sriram.sathy@codiakbio.com.
Mol Cancer Ther ; 20(3): 523-534, 2021 03.
Article en En | MEDLINE | ID: mdl-33443094
The promise of IL12 as a cancer treatment has yet to be fulfilled with multiple tested approaches being limited by unwanted systemic exposure and unpredictable pharmacology. To address these limitations, we generated exoIL12, a novel, engineered exosome therapeutic that displays functional IL12 on the surface of an exosome. IL12 exosomal surface expression was achieved via fusion to the abundant exosomal surface protein PTGFRN resulting in equivalent potency in vitro to recombinant IL12 (rIL12) as demonstrated by IFNγ production. Following intratumoral injection, exoIL12 exhibited prolonged tumor retention and greater antitumor activity than rIL12. Moreover, exoIL12 was significantly more potent than rIL12 in tumor growth inhibition. In the MC38 model, complete responses were observed in 63% of mice treated with exoIL12; in contrast, rIL12 resulted in 0% complete responses at an equivalent IL12 dose. This correlated with dose-dependent increases in tumor antigen-specific CD8+ T cells. Rechallenge studies of exoIL12 complete responder mice showed no tumor regrowth, and depletion of CD8+ T cells completely abrogated antitumor activity of exoIL12. Following intratumoral administration, exoIL12 exhibited 10-fold higher intratumoral exposure than rIL12 and prolonged IFNγ production up to 48 hours. Retained local pharmacology of exoIL12 was further confirmed using subcutaneous injections in nonhuman primates. This work demonstrates that tumor-restricted pharmacology of exoIL12 results in superior in vivo efficacy and immune memory without systemic IL12 exposure and related toxicity. ExoIL12 is a novel cancer therapeutic candidate that overcomes key limitations of rIL12 and thereby creates a therapeutic window for this potent cytokine.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Interleucina-12 / Exosomas Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Mol Cancer Ther Asunto de la revista: ANTINEOPLASICOS Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Interleucina-12 / Exosomas Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Mol Cancer Ther Asunto de la revista: ANTINEOPLASICOS Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos