Last update 01 Nov 2024

KIR x ICOS

Last update 01 Nov 2024

Basic Info

Related Targets

KIRICOS

Drugs associated with KIR x ICOS

KIR x ICOS CD8 Treg Modulator(Mozart)

Target

ICOS x Killer cell immunoglobulin like receptors

Mechanism

ICOS modulators [+1]

Active Org.

Mozart Therapeutics, Inc.Startup

Originator Org.

Mozart Therapeutics, Inc.Startup

Active Indication

Inflammatory Bowel Diseases

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with KIR x ICOS

100 Translational Medicine associated with KIR x ICOS

0 Patents (Medical) associated with KIR x ICOS

Literatures (Medical) associated with KIR x ICOS

15 Oct 2024·Clinical Cancer Research

KIR2DL2/DL3+NKs and Helios+Tregs in Peripheral Blood Predict Nivolumab Response in Patients with Metastatic Renal Cell Cancer

Article

Author: Ieranò, Caterina ; Napolitano, Maria ; Scala, Stefania ; Santagata, Sara ; Coppola, Elisabetta ; Portella, Luigi ; Bello, Anna Maria ; Di Napoli, Marilena ; Rossetti, Sabrina ; D’Alterio, Crescenzo ; Trotta, Anna Maria ; Pignata, Sandro ; Carles, Joan ; Chiodini, Paolo ; Dubois, Bertrand ; Boyle, Helen J. ; Fordellone, Mario ; Caux, Christophe ; Guardascione, Giuseppe ; Rea, Giuseppina ; Feroce, Florinda ; Azzaro, Rosa ; Perdonà, Sisto ; Califano, Daniela

AbstractPurpose:To identify predictive factors of nivolumab sensitivity, peripheral blood NKs and regulatory T-cell (Treg) were evaluated in patients with metastatic renal cell carcinoma (mRCC) enrolled in the REVOLUTION trial.Experimental Design:Fifty-seven mRCCs being treated with nivolumab, as at least second-line of therapy, and 62 healthy donors were longitudinally evaluated (0–1–3–6–12 months) for peripheral NKs and Tregs, phenotype, and function. Multivariable logistic regression was conducted to identify the independent predictors. The 0.632+ internal cross-validation was used to avoid overfitting. The best cutoff value based on a 3-month clinical response was applied to progression-free survival (PFS) and overall survival (OS). Kaplan–Meier curves for PFS and OS were produced.Results:At pretreatment, mRCCs displayed high frequency of NKp46+NKs, NKp30+NKs, KIR2DL1+NKs, KIR2DL2/DL3+NKs, and PD1+NKs with reduced NK degranulation as well as high frequency of Tregs, PD1+Tregs, Helios+Tregs, and ENTPD1+Tregs. Responder patients, identified as a clinical response after 3 months of treatment, presented at pretreatment significantly low CD3+, high KIR2DL2/DL3+NKs, high PD1+Tregs, and high Helios+Tregs. Upon multivariate analysis, only KIR2DL2/DL3NKs and Helios+Tregs held as independent predictors of nivolumab responsiveness. The KIR2DL2/DL3+NKs >35.3% identified patients with longer OS, whereas the Helios+Tregs >34.3% displayed significantly longer PFS. After 1-month of nivolumab, responder patients showed low CD3+, high NKs, KIR2DL2/DL3+NKs, and ICOS+Tregs. Among these subpopulations, CD3+ and KIR2DL2/DL3+NKs held as independent predictors of nivolumab efficacy. Low CD3+ (≤71%) was significantly associated with longer PFS, whereas high KIR2DL2/DL3+NKs (>23.3%) were associated with both PFS and OS.Conclusions:Pretreatment evaluation of Helios+Tregs/KIR2DL2/DL3+NKs and 1-month posttreatment CD3+/ KIR2DL2/DL3+NKs will predict nivolumab response in mRCCs.

01 Oct 2021·European Journal of CancerQ1 · MEDICINE

ICOS is widely expressed in cutaneous T-cell lymphoma and its targeting promotes potent killing of malignant cells

Q1 · MEDICINE

Article

Author: Gorvel, Laurent ; Castellano, Rémy ; Bouabdallah, Réda ; Ortonne, Nicolas ; De Croos, Amandine ; Orlanducci, Florence ; Amatore, Florent ; Schiano, Jean-Marc ; Gaulard, Philippe ; Olive, Daniel ; Grob, Jean-Jacques ; Goubard, Armelle ; Bensussan, Armand ; Bonnet, Nathalie ; Lopez, Marc ; Bagot, Martine ; Delaporte, Emmanuel ; Ingen-Housz-Oro, Saskia

Advanced cutaneous T-cell lymphomas (CTCLs) remain an unmet medical need. Brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate (ADC) linked to monomethyl auristatin E (MMAE), do not deliver significant long-term improvements in patient outcomes.More recently, mogamulizumab and anti-KIR3DL2 provided encouraging results but new targeted therapies are needed.Inducible Co-Stimulator (ICOS), a T-cell costimulatory receptor involved in the development of CTCLs, arouses interest.We used immunohistochem. to study ICOS expression in skin biopsies of 23 patients with early-stage mycosis fungoides (MF), 12 with transformed MF (TMF) and 17 with Sezary syndrome.(SS), at diagnosis or in relapse.ICOS expression by circulating Sezary cells and regulatory T cells (Tregs) in patients with SS was evaluated using flow cytometry and compared to healthy donors (HD) lymphocytes.In 5 patients with SS, we also analyzed concomitant biopsies from involved nodes.We used ICOS+ CTCL cell lines (MyLa, MJ and HUT78), murine xenograft models with MyLa and ICOS+ Patient Derived Xenografts (PDXs) from patients with SS and AITL.ICOS was highly expressed by the cutaneous atypical lymphocytic infiltrates in resp. 61%, 75% and 88% of patients with early-stage MF, TMF and SS, such as in all the involved nodes.Double staining experiments which were performed in both skin and lymph node revealed that ICOS expression appears mainly restricted to neoplastic CD4+ T-cells, with rare ICOS+CD8+ T-cells in the tumor micro-environment.Percentages of ICOS+ Tregs were significantly higher in patients with SS than in HD.In CTCL cell lines, we observed a significant dose-dependent decrease in cell viability in the presence of anti-ICOS-MMAE and anti-ICOS-PBD ADCs. In a mouse xenograft model (MyLa), anti-ICOSMMAE ADCs provided a longer overall survival (OS) than BV (HR=15.2; 95% CI 3.2-71.1; p<0.0006).Finally, in ICOS+ PDXs, anti-ICOS-MMAE ADCs significantly improved OS, and reduced the number of tumor cells in the blood, spleen, and bone marrow.No evidence of ADC toxicity was observed in treated mice.ICOS is a promising therapeutic target because it is expressed both by tumor T-cells and regulatory T-cells.These results could be extended to the spectrum of follicular variant peripheral T-cell lymphomas.

27 Oct 2020·Blood AdvancesQ2 · MEDICINE

ICOS is widely expressed in cutaneous T-cell lymphoma, and its targeting promotes potent killing of malignant cells

Q2 · MEDICINE

Article

Author: Lopez, Marc ; Bagot, Martine ; De Croos, Amandine ; Collette, Yves ; Olive, Daniel ; Ortonne, Nicolas ; Goubard, Armelle ; Grob, Jean-Jacques ; Bensussan, Armand ; Bouabdallah, Réda ; Ingen-Housz-Oro, Saskia ; Gaulard, Philippe ; Bonnet, Nathalie ; Castellano, Rémy ; Amatore, Florent ; Gorvel, Laurent ; Schiano, Jean-Marc ; Salvado, Clémentine ; Orlanducci, Florence ; Berbis, Philippe

AbstractThe treatment of advanced-stage cutaneous T-cell lymphoma (CTCL) remains an unmet medical need. Mogamulizumab, anti-KIR3DL2, and brentuximab vedotin (BV), an anti-CD30 antibody–drug conjugate (ADC) coupled with monomethyl-auristatin-E (MMAE), provided encouraging results, but new targeted therapies are needed. Inducible T-cell costimulator (ICOS), a T-cell costimulatory receptor, is a promising therapeutic target, not only because it is expressed by malignant T cells in CTCL but also because of its connection with the suppressive activity of regulatory T (Treg) cells. Immunohistochemical analysis revealed that ICOS was widely expressed by malignant cells in skin biopsy specimens from 52 patients with mycosis fungoides and Sézary syndrome (SS), as well as in involved node biopsy specimens from patients with SS. Furthermore, flow cytometry demonstrated its strong expression by circulating tumor cells in all our patients with SS. Percentages of ICOS+ Treg cells were significantly higher in patients with SS than in healthy donors. We then investigated the preclinical efficacy of anti-ICOS ADCs generated by coupling murine anti-ICOS monoclonal antibodies with MMAE and pyrrolobenzodiazepine. In 3 CTCL cell lines (Myla, MJ, and HUT78), we observed a significant dose-dependent decrease in cell viability in the presence of anti-ICOS ADCs. In addition, anti-ICOS-MMAE ADCs had an in vitro and in vivo efficacy superior to BV in a mouse xenograft model (MyLa). Finally, we assessed the efficacy of anti-ICOS ADCs in ICOS+ patient-derived xenografts from patients with SS and angioimmunoblastic T-cell lymphoma. Collectively, our findings provide the preliminary basis for a therapeutic trial.

News (Medical) associated with KIR x ICOS

03 May 2024

·www.prnewswire.com

Mozart Therapeutics to Present Pre-clinical Data on KIR x ICOS CD8 Treg Modulator at Immunology 2024 Meeting

Findings highlight the novel mechanism of action and potential for therapeutic activity in highly inflammatory autoimmune disease SEATTLE, May 3, 2024 /PRNewswire/ -- Mozart Therapeutics, the leading developer of CD8 Treg network modulators, today announce the release of new pre-clinical data for their second program, a KIR x ICOS bispecific antibody targeting CD8 regulatory T cells. The data will be presented during the Immunology 2024 meeting, May 3–7 in Chicago, Illinois. Presentation highlights demonstrate KIR x ICOS Modulator: Restores and potentiates CD8 Treg function through binding the inhibitory receptor KIR and the costimulatory receptor ICOS, both expressed on CD8 Treg Selectively activates CD8 Treg with dose-dependent increases in both their prevalence and capacity to eliminate pathogenic CD4 T cells Enhances ICOS signaling only in CD8 Treg and not other ICOS-expressing immune cells Reduces proinflammatory cytokines and improves survival in a highly inflammatory disease model Has acceptable tolerability in initial studies in humanized mice "Our preclinical data underscore the potential of our KIR x ICOS CD8 Treg Modulator as a selective therapeutic approach for highly inflammatory autoimmune diseases, including Crohn's disease and ulcerative colitis. Findings show that the Modulator is selective toward CD8 Treg, efficacious in models of disease, and has an encouraging safety profile," said Dr. Kristine Swiderek, Chief Scientific Officer at Mozart Therapeutics. "The data support further advancement of this promising molecule." Presentation Details: The poster can be accessed from the Mozart Therapeutics website following the May 6 presentation. About KIR x ICOS Modulator Inhibitory killer immunoglobulin-like receptors (KIR) are autoimmune checkpoints expressed on CD8 regulatory T cells, limiting their function of killing pathogenic CD4 T cells. The inducible T cell costimulator (ICOS) is upregulated on activated CD8 Treg and critical to CD8 Treg function. KIR x ICOS is a bispecific antibody targeting CD8 Treg. The molecule aims to restore CD8 Treg function through inhibition of KIR, while promoting ICOS-mediated CD8 Treg activation, in chronic and highly inflammatory autoimmune disease. About Mozart Therapeutics Mozart Therapeutics is focused on developing first-in-class disease-modifying therapies for autoimmune and inflammatory diseases, utilizing a novel approach to restoring immune system homeostasis by targeting the CD8 Treg network. The company is headquartered in Seattle, WA. For more information, visit and follow the company on LinkedIn @Mozart-tx. Media Contact: Julie Rathbun Rathbun Communications [email protected] 206-769-9219 SOURCE Mozart Therapeutics

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