AbstractBackground:The conversion of suitable antibodies into functional CAR-T therapy presents challenges. Traditional methods for antibody discovery and screening face significant bottlenecks, including the difficulty of high-throughput identification of high-quality antibodies with diverse epitope and affinity coverage, also carry a high risk of missing functionally relevant candidates or falsely identify unsuitable candidates.Methods:Here, we introduce CARP (CAR-T AI-powered Rapid high-throughput screening Platform), a novel solution designed to rapidly identify VHHs with clinical potential in CAR structures. Our screening platform was applied for the development of CAR T-cell therapy targeting Cadherin 17 (CDH17). Following immunization of alpacas and llamas, hundreds of CDH17 VHH hits were analyzed using an AI-powered platform for lineage determination (epitope coverage), humanization, and immunogenicity profiling. A library of >400 CDH17 VHHs was screened in serial proliferation tumor cell line co-culture assays simulating long-term tumor-CAR-T interactions to evaluate their target-specific expansion capacity in CAR-T format.Results:After screening and validation of individual VHH candidates, CDH17 CAR hits consistently outperformed VHHs via traditional methods in functional assays, demonstrating superior activity and robustness. Moreover, CARP successfully identified multiple VHHs with identical target binding domain that demonstrated superior target-dependent expansion compared to clinical CDH17 CAR benchmarks and traditionally selected VHHs.Conclusion:Our CAR VHH platform not only accelerates the discovery process by enabling high-throughput screening to identify highly target-dependent and proliferative VHH leads, but also eliminates the need for additional rounds of immunization and immunogenicity assessments once lead VHHs are identified. CARP offers a powerful, efficient approach for uncovering VHHs that enhance CAR-T cell functionality, providing significant promise for advancing CAR-T therapy development.Citation Format:Weihong Wang, Huiyuan Tang, John Lee, Xinhao Wang, Leo Ng, Yong Wang, Toya N. Baral, Jia Yu, Jiaguo Li, Wenfeng Xu. CARP: a high-throughput platform for rapid VHH discovery of potent CAR-T 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 3158.

21 Apr 2025·Cancer Research

Abstract 3173: JL-lightning CAR-T, a next generation non-viral CAR-T without in-vitro culturing procedure, shows high clinical efficacy, good safety with low treatment dosage

Author: Zhu, Hongfan ; Guo, Jun ; Li, Jiaguo ; Lou, Jinxing ; Lin, Zhicai ; Zhang, Jinjing ; Sun, Yan ; Wang, Shuya ; Rong, Lijie ; Liu, Yi ; Qian, Qijun ; Xu, Wenfeng ; Sun, Dan

AbstractBackground:CAR-T with high in vivo proliferation and long persistency could benefit hematologic malignancy patients with low relapse and long survival. Previous studies reveal that CAR-T stemness (T-stem) and exhaustion level are major determinants of CAR-T quality that contribute to clinical outcome. However, conventional manufacturing process with 9-14 days in vitro culture sacrifices T-stem and prolong the vein-to-vein process. Researchers have tried to shorten this process, but many failed due to T-cell activation insufficiency, transfection toxicity, and poor quality control, especially in non-viral transfection.Methods:Two versions of non-viral JL-Lightning-CAR-T fast manufacturing process have been developed to shorten in vitro culture process, V-30h and V-6h. Of note, there is no culture after transfection to enhance CAR-T-stem and in vivo expansion. JL-transposon has been developed and proved with high transfection efficiency and low toxicity on both activated and resting T cells. We generated a tri-targeting CAR-T (BZE2204) using VHHs against CD19, CD22 and BCMA, then evaluated its safety and efficacy with both V-30h and V-6h in vitro and in vivo using Raji orthotropic model. One investigator-initiated trial (IIT) is designed to assess the safety and preliminary efficacy of BZE2204 CAR-T in relapsed/refractory Non-Hopkins Lymphoma (r/r NHL) patients.Results and Conclusion:In vitro experiments showed both versions of BZE2204 exerted strong cytotoxicity on CD19-, CD22- and BCMA-positive tumor cells with high CAR-T cell expansion rates, superior stemness and low exhaustion phenotype compared with conventional CAR-T. V-6h, which has the shortest process, displayed the highest T-stem and proliferation among all groups. In vivo models showed V-30h BZE2204 inhibited tumor growth and significantly prolonged mice lifespan under super low dosage (1E5 CAR-T/mouse). Three r/r NHL patients with high tumor burden were enrolled and infused with the dosage of 40-fold lower than conventional CAR-T. The data showed that CAR-T BZE2204 had promising clinical response with manageable safety profile, two achieved complete remission (CR) within 1 month, and the third patient with a single tumor over 7000mm2 in-size, achieved partial remission (PR) with >80% of tumor shrinkage. Pharmacokinetics data showed high CAR-T proliferation with Cmax of 5066 CAR-T cells/ul and AUC0-28 of 46, 486 cells*d. Our results show JL-Lightning CAR-T achieves high anti-tumor efficacy and good safety in large tumor-burden r/r NHL patients with super low dosage, likely due to short non-viral manufacturing process, high stemness and proliferation, and VHH-based multi-targeting design in CAR-T product. It offers a more effective, affordable and short vein-to-vein process option for hematologic malignancies CAR-T treatment.Citation Format:Shuya Wang, Yan Sun, Jinxing Lou, Hongfan Zhu, Zhicai Lin, Dan Sun, Jiaguo Li, Lijie Rong, Jun Guo, Jinjing Zhang, Yi Liu, Wenfeng Xu, Qijun Qian. JL-lightning CAR-T, a next generation non-viral CAR-T without in-vitro culturing procedure, shows high clinical efficacy, good safety with low treatment dosage [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 3173.

21 Apr 2025·Cancer Research

Abstract 6068: CT111, a novel trispecific PD-1 x CTLA-4 x VEGF single-domain antibody, synergistically targets exhausted T cells and promotes cooperative antitumor effects

Author: Qian, Qijun ; Li, Jiaguo ; Lee, John ; Tang, Huiyuan ; Ng, Leo ; Wang, Yong ; Wang, Weihong ; Wang, Xinhao ; Yu, Jia ; Baral, Toya N. ; Xu, Wenfeng ; Yu, Jing

AbstractBackground:Dual PD-1 and CTLA-4 targeting immunotherapy shows enhanced therapeutic efficacy and is approved across multiple advanced solid tumor indications. In recent clinical trials, combined treatment of anti-PD-(L)1 with anti-VEGF have also been shown to improve clinical outcomes and overcome treatment resistance to either drugs alone. Bispecific antibodies targeting PD-(L)1/CTLA-4 and PD-(L)1/VEGF synergistically potentiates antitumor activity in preclinical models, and more recently, demonstrated enhanced clinical efficacy and tolerability. We developed a de novo, multi-targeting PD-1 x CTLA-4 x VEGF single domain trispecific antibody with enhanced synergistic anti-tumor activity by combining the effects of dual immune checkpoint and VEGF blockade.Methods:Novel function-blocking anti-PD-1, anti-CTLA-4 and anti-VEGF single-domain antibodies generated from protein-immunized camelids were screened, optimized, and humanized using the VHHMAb® AI-powered platform. Multiple VHH leads were combinatorially screened in different Fc-backbone formats for optimal engagement of all three targets. Binding affinity and specificity were evaluated by protein-based ELISA, cell-based FACS and Octet BLI, and ligand blocking activities were measured by competitive ELISA, cell-based FACS and reporter assays. Multitarget interactions and avidity were measured by competitive ELISA, Octet BLI, and cell-based FACS. Bioactivity of PD-1 and CTLA-4 blockade on primary immune cells was evaluated in CMV-recall and SEB assays for cytokine release, and anti-VEGF bioactivity was determined in a HUVEC proliferation assay. Anti-tumor activity of CT111 was assessed in multiple hPBMC-engrafted humanized xenograft tumor models.Results:All three de novo VHH antibodies used as building blocks for CT111 were selected based on strong functional activities that were superior to clinical benchmarks in cell-based assays. CT111 exhibited strong binding and optimal ligand blocking activity to human PD-1, CTLA-4 and VEGF alone and simultaneously in different assay formats. In CMV-recall and SEB stimulation assays, CT111 mediated potent IFN-γ and IL-2 secretion compared to clinical mono-targeting Ab combinations and bispecific benchmarks across multiple donors, and CT111 effectively blocked VEGF-mediated signaling and attenuated HUVEC proliferation. CT111 showed significant antitumor activity compared to clinical benchmarks, including AK112 and AK104, in PBMC humanized tumor models.Conclusion:CT111 is a novel, potential first-in-class single-domain trispecific antibody that can simultaneously target PD-1 and CTLA-4 immune checkpoints on exhausted T cells, while also targeting VEGF-mediated tumor angiogenesis to overcome immune suppression synergistically within solid tumors.Citation Format:John Lee, Huiyuan Tang, Jia Yu, Weihong Wang, Leo Ng, Jing Yu, Yong Wang, Toya N. Baral, Jiaguo Li, Xinhao Wang, Qijun Qian, Wenfeng Xu. CT111, a novel trispecific PD-1 x CTLA-4 x VEGF single-domain antibody, synergistically targets exhausted T cells and promotes cooperative antitumor effects [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 6068.

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Pipeline Snapshot as of 14 May 2025

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

BZE-2203 ( CTLA4 x MSLN x MUC1 x PD-1 )	Solid tumor More	Preclinical
CT111 ( CTLA4 x PD-1 x VEGF )	Solid tumor More	Preclinical
Anti-CD3/TAA T cell engagers ( CD3 x TAA )	Autoimmune Diseases More	Preclinical
BZE-2204 ( BCMA x CD19 x CD22 )	Non-Hodgkin Lymphoma More	Preclinical

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