Topically-applied collagen-binding serum albumin-fused interleukin-4 modulates wound microenvironment in non-healing wounds

Abigail L Lauterbach; Rachel P Wallace; Aaron T Alpar; Kirsten C Refvik; Joseph W Reda; Ako Ishihara; Taryn N Beckman; Anna J Slezak; Yukari Mizukami; Aslan Mansurov; Suzana Gomes; Jun Ishihara; Jeffrey A Hubbell

doi:10.1038/s41536-023-00326-y

Topically-applied collagen-binding serum albumin-fused interleukin-4 modulates wound microenvironment in non-healing wounds

NPJ Regen Med. 2023 Sep 11;8(1):49. doi: 10.1038/s41536-023-00326-y.

Authors

Abigail L Lauterbach¹, Rachel P Wallace¹, Aaron T Alpar¹, Kirsten C Refvik¹, Joseph W Reda¹, Ako Ishihara^{1

2}, Taryn N Beckman³, Anna J Slezak¹, Yukari Mizukami⁴, Aslan Mansurov¹, Suzana Gomes¹, Jun Ishihara^{5

6}, Jeffrey A Hubbell^{7

8

9}

Affiliations

¹ Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, 60637, USA.
² Department of Bioengineering, Imperial College London, London, W12 0BZ, UK.
³ Committee on Molecular Metabolism and Nutrition, University of Chicago, Chicago, IL, 60637, USA.
⁴ Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Honjo, Kumamoto, Japan.
⁵ Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, 60637, USA. j.ishihara@imperial.ac.uk.
⁶ Department of Bioengineering, Imperial College London, London, W12 0BZ, UK. j.ishihara@imperial.ac.uk.
⁷ Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, 60637, USA. jhubbell@uchicago.edu.
⁸ Committee on Cancer Biology, University of Chicago, Chicago, IL, 60637, USA. jhubbell@uchicago.edu.
⁹ Committee on Immunology, University of Chicago, Chicago, IL, 60637, USA. jhubbell@uchicago.edu.

Abstract

Non-healing wounds have a negative impact on quality of life and account for many cases of amputation and even early death among patients. Diabetic patients are the predominate population affected by these non-healing wounds. Despite the significant clinical demand, treatment with biologics has not broadly impacted clinical care. Interleukin-4 (IL-4) is a potent modulator of the immune system, capable of skewing macrophages towards a pro-regeneration phenotype (M2) and promoting angiogenesis, but can be toxic after frequent administration and is limited by its short half-life and low bioavailability. Here, we demonstrate the design and characterization of an engineered recombinant interleukin-4 construct. We utilize this collagen-binding, serum albumin-fused IL-4 variant (CBD-SA-IL-4) delivered in a hyaluronic acid (HA)-based gel for localized application of IL-4 to dermal wounds in a type 2 diabetic mouse model known for poor healing as proof-of-concept for improved tissue repair. Our studies indicate that CBD-SA-IL-4 is retained within the wound and can modulate the wound microenvironment through induction of M2 macrophages and angiogenesis. CBD-SA-IL-4 treatment significantly accelerated wound healing compared to native IL-4 and HA vehicle treatment without inducing systemic side effects. This CBD-SA-IL-4 construct can address the underlying immune dysfunction present in the non-healing wound, leading to more effective tissue healing in the clinic.