Author: King, Alastair J. ; Kim, Kyumhyuk ; Neethling, Francisca ; Anton, Korneelia ; Ustav, Anu ; Virumäe, Kai ; Ustav, Mart ; Tahk, Siret ; Teyra, Joan ; Morizumi, Takefumi ; Hermet, Paule ; Pau, Robin ; Männik, Andres ; Ernst, Oliver

AbstractBackground:Cancer cells often exhibit upregulated glucose metabolism to support their abnormal growth and division. Targeting the cancer-specific glucose transporter GLUT-1 offers a promising strategy to limit glucose uptake and disrupt tumor metabolism. Unlike small molecule inhibitors, monoclonal antibodies provide a unique opportunity to selectively target complex multi-pass membrane transporters. This study presents the development of highly specific antibodies that recognize GLUT-1 glycovariants, effectively blocking GLUT-1 function in cancer cells while preserving glucose transport across the blood-brain barrier.Methods:GLUT-1-specific monoclonal antibodies were generated using GLUT-1-displaying virus-like particles (VLPs) as immunogens. Chickens were chosen for immunization due to their ability to produce antibodies against highly conserved multi-transmembrane proteins. Antibody discovery was conducted using HybriFree B cell cloning technology and phage display. Functional screens included assays for 2-deoxyglucose uptake inhibition and cancer cell proliferation.Results:The identified antibodies bind GLUT-1 with nanomolar EC50 values and exhibit no cross-reactivity with other glucose transporters. The lead candidate, ICO-33, inhibits glucose uptake and reprograms GLUT-1-dependent cancer cells to rely on oxidative phosphorylation (OXPHOS). This metabolic shift synergizes with OXPHOS inhibitors, resulting in significant cancer cell growth inhibition at doses subtherapeutic as monotherapies. In vivo, the combination of ICO-33 and an OXPHOS inhibitor was well-tolerated and led to substantial tumor growth suppression in colorectal and pancreatic cancer models. Importantly, ICO-33 preserves glucose uptake in the brain, minimizing systemic toxicities.Conclusions:This study highlights the discovery of GLUT-1-targeting monoclonal antibodies with high specificity and efficacy. The lead antibody, ICO-33, effectively restricts glucose uptake in cancer cells and enhances sensitivity to OXPHOS inhibitors, demonstrating its potential as a candidate for clinical development in cancer therapy.Citation Format:Siret Tahk, Paule Hermet, Kyumhyuk Kim, Takefumi Morizumi, Anu Ustav, Kai Virumäe, Robin Pau, Korneelia Anton, Alastair J. King, Francisca Neethling, Andres Männik, Joan Teyra, Oliver Ernst, Mart Ustav. Highly specific GLUT-1 inhibiting antibodies for the treatment of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4792.

21 Apr 2025·Cancer Research

Abstract 4814: Development of a novel claudin-6-targeting CAR-T cell

Author: Hermet, Paule ; Plaas, Mario ; Pau, Robin ; Teyra, Joan ; Mahlakōiv, Tanel ; Ustav, Anu ; Männik, Andres ; Tahk, Siret ; Shahpazir, Ana ; Kivi, Gaily ; Ustav, Mart

AbstractChimeric antigen receptor (CAR) T cell therapies have achieved remarkable efficacy in treating B cell malignancies but have shown limited clinical success in patients with solid tumors. A key challenge in advancing these therapies lies in the identification and targeting of highly tumor-specific antigens to ensure both safety and efficacy. In this study, we employed HybriFree B-cell cloning technology and phage display to discover antibodies targeting Claudin-6 (CLDN6), an oncofetal protein selectively expressed in subsets of ovarian, lung, endometrial, and testicular cancers, with minimal or no expression in healthy adult tissues.To generate a robust immune response, chickens were immunized with virus-like particles (VLPs) displaying a high-density presentation of transmembrane CLDN6. Monoclonal antibodies specific to CLDN6 were subsequently screened for their specificity towards CLDN6 using VLPs bearing other Claudin family members. The most promising specific binders that were able to discriminate between binding of CLDN6 and CLDN9 were humanized via the Qumanize platform and incorporated into a second-generation CAR construct with a 4-1BB costimulatory domain and CD3ζ signaling domain.CLDN6-specific CAR T cells were then generated and evaluated for their cytotoxicity in tumor models of ovarian, lung, and gastric cancers. Two CLDN6-specific CARs exhibited highly specific recognition and efficient lysis of cancer cells endogenously expressing CLDN6. Within 24 hours of co-culture, CLDN6 CAR T cells eliminated 80% of PA-1 cells and 60% of OV-90 cells. To assess T cell immune activation, cytokine secretion was measured upon co-culture with various target cells. Notably, IFN-γ secretion was observed exclusively when CLDN6 CAR T cells were co-cultured with CLDN6-positive targets, confirming their antigen specificity.This study underscores the utility of HybriFree technology and the Qumanize platform in generating highly specific and high-affinity CARs for tumor targeting. These findings present a promising avenue for developing next-generation immunotherapies for CLDN6-expressing solid tumors.Citation Format:Ana Shahpazir, Siret Tahk, Paule Hermet, Anu Ustav, Robin Pau, Gaily Kivi, Mario Plaas, Andres Männik, Joan Teyra, Mart Ustav, Tanel Mahlakōiv. Development of a novel claudin-6-targeting CAR-T cell [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4814.

21 Apr 2025·Cancer Research

Abstract 3407: Development of bispecific antibodies targeting claudin-6 for precision cancer therapy

Author: Mahlakōiv, Tanel ; Plaas, Mario ; Teyra, Joan ; Kivi, Gaily ; Männik, Andres ; Tahk, Siret ; Pau, Robin ; Hermet, Paule ; Ustav, Mart ; Ustav, Anu ; Shahpazir, Ana

AbstractBackground:Claudin 6 (CLDN6), a tight junction protein, is an oncofetal antigen with limited expression in adult tissues but aberrantly overexpressed in several cancers, including ovarian, testicular, and gastric tumors. Its tumor-specific expression and critical role in maintaining cell adhesion make CLDN6 a compelling target for cancer therapy. Recent studies have linked CLDN6 to tumor progression, metastasis, and chemoresistance, highlighting its potential as both a biomarker and a therapeutic target in precision oncology. This study presents the development of bispecific antibodies for the treatment of CLDN6-positive tumors.Methods:Monoclonal antibodies specific to CLDN6 were generated using virus-like particles (VLPs) displaying CLDN6 as immunogens. Chickens were selected for immunization due to their ability to produce antibodies against highly conserved, multi-transmembrane proteins. Antibody discovery was performed using HybriFree B cell cloning technology and phage display platforms.Results:Bispecific antibodies that specifically recognize CLDN6 and CD3 were developed and evaluated for their effectiveness in killing CLDN6-positive cells while sparing CLDN6-negative cells. Various bispecific antibody formats were assessed, showing differences in non-specific T-cell activation. These findings underscore the importance of selecting appropriate bispecific antibody modalities to achieve maximum therapeutic potency while ensuring a favorable safety profile. The functionality and potency of these novel bispecific antibodies were further demonstrated in vivo using ovarian cancer xenograft models.Conclusions:This study highlights the development of novel bispecific antibodies targeting CLDN6 and CD3, emphasizing their superior safety profile. The use of specifically engineered antibody modalities and highly selective CLDN6 binders ensures minimal cross-reactivity with other homologous family members. These findings support the potential of these bispecific antibodies as a promising therapeutic approach for CLDN6-positive cancers.Citation Format:Siret Tahk, Paule Hermet, Anu Ustav, Robin Pau, Ana Shahpazir, Mario Plaas, Gaily Kivi, Andres Männik, Joan Teyra, Tanel Mahlakōiv, Mart Ustav. Development of bispecific antibodies targeting claudin-6 for precision cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3407.

100 Deals associated with Icosagen Cell Factory OÜ

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Drug(Targets)	Indications	Global Highest Phase

Claudin-6-Targeting CAR-T Cell(Icosagen Cell Factory) ( CLDN6 )	CLDN6-positive Solid Tumors More	Preclinical
CLDN6/CD3 bispecific antibody(Icosagen) ( CD3 x CLDN6 )	CLDN6-positive Solid Tumors More	Preclinical
Targeting ADORA2A monoclonal antibody (Icosagen) ( A2aR )	Neoplasms More	Preclinical

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