AbstractTissue factor (TF) plays important roles in the hemostasis process. Through forming complex with factor (F) VII/VIIa, TF helps to initiate the blood coagulation process that protects vital organs from excessive bleeding. Under pathological conditions TF could also be involved in thrombosis. Furthermore, TF has functions beyond hemostasis such as signaling. TF is involved in many aspects of cancer transformation such as aberrant signaling, metastasis, and tumor angiogenesis. TF has been found to overexpress in multiple cancers including cervical, pancreatic, lung, head and neck, and prostate cancers, etc. Therapeutics targeting TF has achieved success with most notably the recent approval of Tisotumab Vedotin against cervical cancer. We report here the early phase development of an anti-TF ADC. Our in-house phage display library was employed to isolate a panel of fully human anti-TF antibodies. They vary in binding epitope and affinity allowing the opportunity to evaluate the optimum combination of both to achieve superior efficacy and safety. We found that the binding epitope plays a significant role in the antibody-mediated internalization, whereas within the same binding bin, antibody affinity and internalization may not have a direct correlation. One such antibody, 1E11, has a similar epitope to Tisotumab. It has a modest binding affinity (KD=68 nM) compared to other internal candidates as well as Tisotumab, yet it displayed similar or superior internalization efficiency and ADC mediated cell killing against multiple TF positive cell lines in vitro. In several CDX in vivo models tested so far, 1E11 based ADC showed comparable or superior activities to Tisotumab carrying the same linker/payload. Significantly, while Tisotumab displayed significant disruption of TF/factor VII interaction, a potential cause for excessive bleeding observed in clinics using Tisotumab Vedotin, 1E11 showed little or no such activities. These highly relevant function and safety features of 1E11-based ADC plus its excellent developability profile suggest that it is a promising candidate for further development into various ADC based therapeutics either used alone or in combination with other therapeutics.Citation Format:Xiaodong Xiao, Zhidi Pan, Zhangyi Song, Haiyang Yin, Hua Jiang, Yueqing Xie, Jianwei Zhu. Development of an anti-TF ADC with a potentially improved therapeutic index [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 348.

21 Apr 2025·Cancer Research

Abstract 2230: Persistent elimination of tumors via balanced regulation of immune signals

Author: Jiang, Hua ; Yuan, Yuan ; Zhu, Jianwei ; Xie, Yueqing ; Han, Lei ; Xiao, Xiaodong

AbstractDespite its success, there are still numerous unmet clinical needs in cancer immunotherapy. Many patients failed to respond due to the lack of effective and properly regulated T cell stimulation. Molecules capable of inhibiting multiple immune checkpoints, enhancing the co-stimulatory signals on T cells to “revive” the tumor antigen-specific T cell response, as well as sustaining the responses to prevent the recurrence of the tumor are highly desirable. Here we report a Fc-based, tripartite, multifunctional fusion protein JLM019 that has been rationally designed to integrate the multiple mechanisms of PD-1/PD-Ligands checkpoint inhibition and T cell co-stimulations through CD80-mediated signaling. Fused at the C-terminus of the Fc fragment, structure-guided mutations A132L and Loop15 were introduced into the human PD-1 ectodomain to improve affinity with its ligands. Fused at the N-terminus, the wild-type CD80 provided a canonical co-stimulatory signal compared to hyperreactive anti-CD28 agonistic antibodies. Combined effect of PD-1 signaling blockade and balanced T cell activation through CD80 binding with CTLA4/CD28 by JLM019 led to persistent elimination of wide spectrum of tumors, including tumors with no PD-L1 expression, or those resistant to conventional PD-1 checkpoint inhibitors in CDX models. JLM019 acts not only on the tumor but also through activating tumor-specific T cells that depend on other APCs and/or through PD-L2 signaling. Significantly, JLM019 treatment induced effective immune memory, which was confirmed by experiments using transferred splenocytes from cured mice that not only prevented tumor initiation but also eliminated tumors in the established tumor-bearing mice. The sophisticated mechanism of the action by JLM019 is explored and discussed. In summary, we developed an immune signal regulator JLM019 that can modulate immune signaling against advanced tumors in a potent yet well-balanced manner. Pre-clinical toxicity and PK/PD studies in cynomolgus monkey have shown a promising safety and toxicity profile, with a dose up to 100mg/kg being tolerated. These encouraging results prompted us to advance JLM019 for clinical studies in humans.Citation Format:Xiaodong Xiao, Lei Han, Yuan Yuan, Hua Jiang, Yueqing Xie, Jianwei Zhu. Persistent elimination of tumors via balanced regulation of immune signals [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 2230.

21 Apr 2025·Cancer Research

Abstract 6021: Development of JLF025, an anti-mesothelin T cell engager optimized for efficacy and safety

Author: Zhu, Jianwei ; Song, Zhangyi ; Wang, Shusheng ; Yang, Kaiyong ; Wang, Zhenyu ; Pan, Zhidi ; Huang, Haiqiu ; Li, Fengzhi ; Jiang, Hua ; Yue, Yali ; Liu, Junjun ; Xiao, Xiaodong ; Xie, Yueqing

AbstractMesothelin (MSLN) is a GPI-anchored glycoprotein that is overexpressed in several solid tumors including mesothelioma, pancreatic cancer, ovarian cancer, non-small cell lung cancer, biliary cancer, and triple negative breast cancer with limited expression in normal tissues. This expression profile makes MSLN an attractive target for cancer immunotherapy. m912 antibody that has demonstrated positive effect in CAR T format in clinics is derived from a fully human Fab library. It has a 100% germline sequence, but its binding affinity is relatively poor (KD around 60 nM). To expand applications of the m912 to include the T-cell engager format, we used phage display to improve m912 affinity, and further, developed a bivalent T-cell engaging bispecific format by fusing the humanized OKT3 scFv to the C-terminus of the light chain. When the final lead with a KD of 1.4 nM was incorporated into this format, the resulting bispecific antibody JLF025 showed high potency in T-cell activation and T-cell dependent cytotoxicity in vitro. Interestingly, the cytotoxicity induced by MSLN-490 was not affected by soluble MSLN at a level found in cancer patient sera. Using a co-grafting mouse model in which a mixture of MSLN-positive NCI-N87 cancer cells and human PBMCs was co-injected with JLF025, we demonstrated that JLF025 exhibited a remarkable tumor suppressing activity. The potent tumor suppressing activity was also observed in a xenograft model in which PBMCs were not co-grafted with tumor cells but delivered from the periphery. In addition, combination of MSLN-490 with Atezolizumab or a chemotherapy drug paclitaxel produced a synergistic effect on tumor inhibition and more T cells were found infiltrated into tumors in the combo groups. In hMSLN and hCD3 double knock-in mouse, JLF025 demonstrated acceptable safety profiles. Thus, combination of JLF025 with immune checkpoint inhibitors and chemotherapy drugs represents a promising cancer treatment strategy and could be considered for future clinical trials.Citation Format:Xiaodong Xiao, Zhidi Pan, Junjun Liu, Yali Yue, Fengzhi Li, Shusheng Wang, Haiqiu Huang, Kaiyong Yang, Zhangyi Song, Zhenyu Wang, Hua Jiang, Yueqing Xie, Jianwei Zhu. Development of JLF025, an anti-mesothelin T cell engager optimized for efficacy and safety [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 6021.

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