Browsing by Author "Hsu, Eric Jonathan"

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    A Cytokine Receptor Masked IL-2 Prodrug Selectively Activates Tumor-Infiltrating Lymphocytes for Potent Antitumor Therapy
    (August 2021) Hsu, Eric Jonathan; Zhang, Chengcheng "Alec"; Farrar, J. David; Malladi, Srinivas; Yan, Nan; Fu, Yang-Xin
    Cancers are very difficult to treat, and many cancer patients fail to respond to numerous standard of care therapies. Many of these tumors have been observed to lack functional CD8 T cells, which have been observed to be correlated with improved patient prognosis. One of the main strategies to combat the lack of functional tumor infiltrating immune cells is to treat patients with immune stimulating cytokines such as interleukin-2 (IL-2). As a potent lymphocyte activator, IL-2 is an FDA approved treatment for multiple metastatic cancers. However, its clinical use is limited by short half-life, low potency, and severe in vivo toxicity. Current IL-2 engineering strategies exhibit evidence of peripheral cytotoxicity. Here, limitations of both recombinant IL-2 and these next generation IL-2 variants are addressed through the engineering of a novel IL-2 prodrug (ProIL2). Numerous designs of ProIL2 were designed, engineered, and tested until a final optimal construct was synthesized. The activity of a CD8 T cell-preferential IL-2 mutein/Fc fusion protein is masked with IL2 receptor beta linked to a tumor-associated protease substrate. ProIL2 restores activity after cleavage by tumor-associated enzymes, and preferentially activates inside tumors, where it expands antigen-specific CD8 T cells. This significantly reduces IL-2 toxicity and mortality without compromising antitumor efficacy. ProIL2 also overcomes resistance of cancers to immune checkpoint blockade. Furthermore, neoadjuvant ProIL2 treatment can eliminate metastatic cancer through an abscopal effect. Lastly, ProIL2 can also synergize with radiation therapy to more effectively control both primary and metastatic cancer. Further protein engineering strategies are being implemented to overcome potential limitations of ProIL2. Taken together, this approach presents an effective tumor targeting therapy with reduced toxicity.