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709 Exosome surface display of IL-12 results in tumor-retained pharmacology with superior potency and limited systemic exposure
  1. Nuruddeen Lewis,
  2. Chang Ling Sia,
  3. Katherine Kirwin,
  4. Sonya Haupt,
  5. Gauri Mahimkar,
  6. Tong Zi,
  7. Ke Xu,
  8. Kevin Dooley,
  9. Su Chul Jang,
  10. Bryan Choi,
  11. Andrew Grube,
  12. Christine McCoy,
  13. Jorge Sanchez-Salazar,
  14. Michael Doherty,
  15. Scott Estes,
  16. Kyriakos Economides,
  17. Douglas Williams and
  18. Sriram Sathyanaryanan
  1. Codiak BiSciences, Andover, MA, USA


Background The promise of Interleukin-12 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 exoIL-12™, a novel, engineered-exosome therapeutic that displays functional IL-12 on the surface of an exosome.

Methods IL-12 exosomal surface expression was achieved via fusion to the abundant exosomal surface protein PTGFRN. Potency was assessed in vitro using human PBMCs or murine splenocytes and in vivo using mouse subcutaneous tumor models. Local versus systemic pharmacology was determined with intratumoral injection in mice and subcutaneous injection in monkeys. All studies were benchmarked against recombinant IL-12 (rIL-12).

Results Exosomes engineered to express either murine or human IL-12 had equivalent potency in vitro to rIL-12 as demonstrated by IFNγ production. Following intratumoral injection, exoIL-12 exhibited prolonged tumor retention and greater antitumor activity than rIL-12. Moreover, exoIL-12 was 100-fold more potent than rIL-12 in tumor growth inhibition. In the MC38 tumor model, complete responses were observed in 63% of mice treated with exoIL-12; in contrast, rIL-12 resulted in 0% complete responses at an equivalent IL-12 dose. This correlated with dose-dependent increases in tumor antigen-specific CD8+ T cells. Re-challenge studies of exoIL-12 in complete responder mice showed no tumor regrowth. Moreover, depletion of CD8+ T cells completely abrogated the antitumor activity of exoIL-12. Following intratumoral administration, exoIL-12 exhibited 10-fold higher intratumoral exposure than rIL-12 and prolonged IFNγ production up to 48 hr. Retained, local pharmacology of exoIL-12 was further confirmed using subcutaneous injections in non-human primates.

Conclusions This work demonstrates that tumor-restricted pharmacology of exoIL-12 results in superior in vivo efficacy and immune memory without systemic IL-12 exposure and related toxicity. exoIL-12 is a novel cancer therapeutic candidate that has the potential to overcome key limitations of rIL-12 and thereby create a therapeutic window for this potent cytokine.

Ethics Approval All animals were maintained and treated at the animal care facility of Codiak Biosciences in accordance with the regulations and guidelines of the Institutional Animal Care and Use Committee (CB2017-001).

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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