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Cancer Immunol Res. 2024 Jun 6. doi: 10.1158/2326-6066.CIR-23-0636. Online ahead of print.
Naveen K Mehta 1, Kavya Rakhra 1, Kristan A Meetze 1, Bochong Li 1, Noor Momin 2, Jason Yh Chang 1, K Dane Wittrup 3, Patrick A Baeuerle 4, Jennifer S Michaelson 1
Affiliations expand
- PMID: 38842347
- DOI: 10.1158/2326-6066.CIR-23-0636
Abstract
Despite clinical evidence of antitumor activity, the development of cytokine therapies has been hampered by a narrow therapeutic window and limited response rates. Two cytokines of high interest for clinical development are interleukin 2 (IL-2) and interleukin 12 (IL-12), which potently synergize to promote the activation and proliferation of T cells and natural killer (NK) cells. However, the only approved human IL-2 therapy, Proleukin, is rarely used in the clinic due to systemic toxicities, and no IL-12 product has been approved to date due to severe dose-limiting toxicities. Here, we describe CLN-617, a first-in-class therapeutic for intratumoral (IT) injection that co-delivers IL-2 and IL-12 on a single molecule in a safe and effective manner. CLN-617 is a single-chain fusion protein comprised of IL-2, leukocyte-associated immunoglobulin-like receptor 2 (LAIR2), human serum albumin (HSA), and IL-12. LAIR2 and HSA function to retain CLN-617 in the treated tumor by binding collagen and increasing molecular weight, respectively. We found that IT administration of a murine surrogate of CLN-617, mCLN-617, eradicated established treated and untreated tumors in syngeneic models, significantly improved response to anti-PD1 checkpoint therapy, and generated a robust abscopal response dependent on cellular immunity and antigen cross-presentation. CLN-617 is being evaluated in a clinical trial in patients with advanced solid tumors (NCT06035744).