Author: Yang, Hao ; Chen, Zhuo ; Lu, Xiaofeng ; Tao, Ze ; Li, Jing ; Chen, Yuzhe ; Chen, Jie ; She, Tianshan ; Huang, Yunchuan ; Lu, Hongyu ; Zhu, Hong ; Ren, Enhui

As T and NK cell exhaustion is attributed to increased expression of immune checkpoints and decreased production of proliferative cytokines by these cells, immune checkpoint-targeted delivery of proliferative cytokines might induce robust and sustained antitumor immune responses. Here, the expression profile of NKG2A was first found to be narrower than that of PD-1 in tumor-infiltrated immune cells. Moreover, unlike PD-1, NKG2A was predominantly co-expressed with IL-2Rβγ in tumor-infiltrated CD8⁺ T and NK cells, but not in Tregs, suggesting that NKG2A might be an ideal target for delivery of IL-2Rβγ agonists to overcome T and NK exhausting. For NKG2A-targeted delivery of an IL-2Rβγ agonist, a single molecule of de novo designed N215 endowed with Immunoglobin G(IgG)-binding ability was coupled to an antibody against NKG2A (αNKG2A) to produce αNKG2A-N215. NKG2A- and IL-2Rβγ-binding were well preserved in αNKG2A-N215, allowing αNKG2A-N215 to act as both an immune checkpoint inhibitor and a T and NK cell stimulator. Intravenously injected αNKG2A-N215 predominantly induced expansion of tumor-infiltrated CD8⁺ T and NK cells while showing little stimulation of Tregs. Compared with the separate combination using αNKG2A and N215, αNKG2A-N215 exerted a greater antitumor effect in mice bearing MC38 or B16/F1 tumors. 50% of mice bearing MC38 tumors were cured by αNKG2A-N215, and long-term immunological memory against the tumor was induced in these mice. These results indicate that NKG2A is another ideal target for delivery of an IL-2Rβγ agonist, and αNKG2A-N215, with specificities for both NKG2A and IL-2Rβγ, might be developed as a novel agent for immunotherapy.

Scientific ReportsQ3 · CROSS-FIELD

A bispecific antibody agonist of the IL-2 heterodimeric receptor preferentially promotes in vivo expansion of CD8 and NK cells

Q3 · CROSS-FIELD

ArticleOA

Author: Schellenberger, Ute ; Sankaran, Preethi ; Buelow, Roland ; Davison, Laura M ; Loughlin, Kaitlyn ; Boudreau, Andrew A ; Avanzino, Brian C ; Cuturi, Maria-Cristina ; Hartstein, Sharon ; Ahmil, Ghenima ; Chang, Karen ; Iyer, Suhasini ; Harris, Katherine E ; Basappa, Harish Medlari ; Ho, Dennis M ; Allen, Nicole S ; Malik-Chaudhry, Harbani K ; Balasubramani, Aarti ; Trinklein, Nathan D ; Lorentsen, Kyle J ; Rangaswamy, Udaya S

AbstractThe use of recombinant interleukin-2 (IL-2) as a therapeutic protein has been limited by significant toxicities despite its demonstrated ability to induce durable tumor-regression in cancer patients. The adverse events and limited efficacy of IL-2 treatment are due to the preferential binding of IL-2 to cells that express the high-affinity, trimeric receptor, IL-2Rαβγ such as endothelial cells and T-regulatory cells, respectively. Here, we describe a novel bispecific heavy-chain only antibody which binds to and activates signaling through the heterodimeric IL-2Rβγ receptor complex that is expressed on resting T-cells and NK cells. By avoiding binding to IL-2Rα, this molecule circumvents the preferential T-reg activation of native IL-2, while maintaining the robust stimulatory effects on T-cells and NK-cells in vitro. In vivo studies in both mice and cynomolgus monkeys confirm the molecule’s in vivo biological activity, extended pharmacodynamics due to the Fc portion of the molecule, and enhanced safety profile. Together, these results demonstrate that the bispecific antibody is a safe and effective IL-2R agonist that harnesses the benefits of the IL-2 signaling pathway as a potential anti-cancer therapy.

Signal Transduction and Targeted Therapy

Neoleukin-2/15-armored CAR-NK cells sustain superior therapeutic efficacy in solid tumors via c-Myc/NRF1 activation

Article

Author: Huang, Mingyan ; Liu, Yanfang ; Liu, Qiuyan ; Qian, Yuping ; Guo, Meng ; Luo, Jianhua ; Cao, Xuetao

AbstractAdoptive transfer of chimeric antigen receptor (CAR)-modified natural killer (NK) cells represents a transformative approach that has significantly advanced clinical outcomes in patients with malignant hematological conditions. However, the efficacy of CAR-NK cells in treating solid tumors is limited by their exhaustion, impaired infiltration and poor persistence in the immunosuppressive tumor microenvironment (TME). As NK cell functional states are associated with IL-2 cascade, we engineered mesothelin-specific CAR-NK cells that secrete neoleukin-2/15 (Neo-2/15), an IL-2Rβγ agonist, to resist immunosuppressive polarization within TME. The adoptively transferred Neo-2/15-armored CAR-NK cells exhibited enhanced cytotoxicity, less exhaustion and longer persistence within TME, thereby having superior antitumor activity against pancreatic cancer and ovarian cancer. Mechanistically, Neo-2/15 provided sustained and enhanced downstream IL-2 receptor signaling, which promotes the expression of c-Myc and nuclear respiratory factor 1 (NRF1) in CAR-NK cells. This upregulation was crucial for maintaining mitochondrial adaptability and metabolic resilience, ultimately leading to increased cytotoxicity and pronounced persistence of CAR-NK cells within the TME. The resistance against TME immunosuppressive polarization necessitated the upregulation of NRF1, which is essential to the augmentative effects elicited by Neo-2/15. Overexpression of NRF1 significantly bolsters the antitumor efficacy of CAR-NK cells both in vitro and in vivo, with increased ATP production. Collectively, Neo-2/15-expressing CAR-NK cells exerts superior antitumor effects by exhaustion-resistance and longer survival in solid tumors.

100 Deals associated with TNB-409

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Phase 1	United States	Amgen, Inc.	19 Oct 2021
Neoplasms	Preclinical	United States	TeneoBio, Inc.	19 May 2021

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