Phase 1b/2 study of GX-I7 plus pembrolizumab in patients with refractory or recurrent (R/R) metastatic triple-negative breast cancer (mTNBC): The KEYNOTE-899 Study.

Sohn, Joohyuk; Kim, Gun Min; Lee, Keun Seok; Kim, Sung‐Bae; Kim, Jee Hung; Ahn, Hee Kyung; LEE, JIEUN; Park, Kyong Hwa; Kim, Jee Hyun; Lee, Kyoung Eun; Shin, Eui-Cheol; Park, Su–Hyung; Yang, Se Hwan; Heo, MinKyu; Woo, Jung Won; Sung, Young Chul; Im, Young Hyuck

doi:10.1200/jco.2022.40.16_suppl.1081

Cited by 2 publications

(2 citation statements)

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“…Efineptakin alfa has achieved clinical responses (partial and complete) when combined with CPI in immunologically cold tumor types and tumors that are relapsed/refractory to prior treatments. [29,[32][33][34][35].…”

Section: Introductionmentioning

confidence: 99%

A mechanistically novel peptide agonist of the IL-7 receptor that addresses limitations of IL-7 cytokine therapy

Dower,

Park,

Bakker

et al. 2023

PLoS ONE

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Interleukin (IL)-7 is broadly active on T-cell populations, and modified versions have been clinically evaluated for a variety of therapeutic applications, including cancer, lymphopenia, and infectious diseases; and found to be relatively well-tolerated and biologically active. Here we describe novel IL-7R agonists that are unrelated in structure to IL-7, bind to the receptor subunits differently from IL-7, but closely emulate IL-7 biology. The small size, low structural complexity, and the natural amino acid composition of the pharmacologically active peptide MDK1472 allows facile incorporation into protein structures, such as the IgG2-Fc fusion MDK-703. This molecule possesses properties potentially better suited to therapeutic applications than native IL-7 or its derivatives. We compared these compounds with IL-7 for immune cell selectivity, induction of IL-7R signaling, receptor-mediated internalization, proliferation, and generation of immune cell phenotypes in human and non-human primate (NHP) peripheral blood cells in vitro; and found them to be similar in biological activity to IL-7. In cynomolgus macaques, MDK-703 exhibits a circulating half-life of 46 hr and produces sustained T-cell expansion characteristic of IL-7 treatment. In the huCD34+-engrafted NSG mouse model of the human immune system, MDK-703 induces an immune cell profile very similar to that generated by IL-7-derived compounds; including the pronounced expansion of memory T-cells, particularly the population of stem-like memory T-cells (Tscm) which may be important for anti-tumor activities reported with IL-7 treatment. Clinical administration of IL-7 and modified variants has been reported to induce anti-drug antibodies (ADAs), including IL-7 neutralizing antibodies. The novel peptide agonist reported here scores very low in predicted immunogenicity, and because the peptide lacks sequence similarity with IL-7, the problematic immunogenic neutralization of endogenous cytokine should not occur. The properties we report here implicate MDK-703 as a candidate for clinical evaluation in oncology, anti-viral and other infectious disease, vaccine enhancement, and treatment of lymphopenia.

show abstract

Section: Introductionmentioning

confidence: 99%

A mechanistically novel peptide agonist of the IL-7 receptor that addresses limitations of IL-7 cytokine therapy

Dower,

Park,

Bakker

et al. 2023

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…In various clinical studies of efineptakin alfa in combination with a CPI, increased T-cell proliferation in the periphery, and objective responses have been observed in immunologically cold tumor types (microsatellite stable colorectal cancer, pancreatic ductal adenocarcinoma) and tumor types that are relapsed/refractory to prior treatments (triple negative breast cancer, nonsmall cell lung cancer, and small cell lung cancer) [29][30][31][32][33].…”

Section: Introductionmentioning

confidence: 99%

A mechanistically novel peptide agonist of the IL-7 receptor that addresses limitations of IL-7 cytokine therapy

Dower

Park

Bakker

et al. 2023

Preprint

View full text Add to dashboard Cite

Interleukin-7 (IL-7) is broadly active on T-cell populations, and modified versions have been clinically evaluated for a variety of therapeutic applications, including cancer, lymphopenia and infectious disease; and found to be relatively well-tolerated and biologically active. Here we describe novel IL-7R agonists that are unrelated in structure to IL-7, bind to the receptor subunits differently from IL-7, but closely emulate IL-7 biology. The small size, low structural complexity, and the natural amino acid composition of the pharmacologically active peptide MDK1472 allows facile incorporation into protein structures, such as the IgG2-Fc fusion MDK-703. This molecule possesses properties potentially better suited to therapeutic applications than native IL-7 or its derivatives. We compared these compounds with IL-7 for immune cell selectivity, induction of IL-7R signaling, receptor-mediated internalization, proliferation, and generation of immune cell phenotypes in human and non-human primate (NHP) peripheral blood cells in vitro; and found them to be similar in biological activity to IL-7. In cynomolgus macaques, MDK-703 exhibits a circulating half-life of 46 hr, and produces sustained T-cell expansion characteristic of IL-7 treatment. In the huCD34+-engrafted NSG mouse model of the human immune system, MDK-703 induces an immune cell profile very similar to that generated by IL-7-derived compounds; including the pronounced expansion of memory T-cells, particularly the population of stem-like memory T-cells (Tscm), which may be important for anti-tumor activities reported with IL-7 treatment. Clinical administration of IL-7 and modified variants has been reported to induce anti-drug antibodies (ADAs), including IL-7 neutralizing antibodies. The novel peptide agonist reported here scores very low in predicted immunogenicity, and because the peptide agonists lack sequence similarity with IL-7, the problematic immunogenic neutralization of endogenous cytokine should not occur.

show abstract

Phase 1b/2 study of GX-I7 plus pembrolizumab in patients with refractory or recurrent (R/R) metastatic triple-negative breast cancer (mTNBC): The KEYNOTE-899 Study.

Cited by 2 publications

References 0 publications

A mechanistically novel peptide agonist of the IL-7 receptor that addresses limitations of IL-7 cytokine therapy

A mechanistically novel peptide agonist of the IL-7 receptor that addresses limitations of IL-7 cytokine therapy

A mechanistically novel peptide agonist of the IL-7 receptor that addresses limitations of IL-7 cytokine therapy

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