Jiangsu T-mab BioPharma (China)

This study was conducted to investigate the effects of a Chinese herbal medicine compound microecological agent (C-MEA) on the egg production performance, ovarian follicle development, ovary transcriptome, and cecal microbiota of caged laying ducks. A total of 108 black Muscovy ducks (150 days old) were randomly divided into three groups for 30 days in a formal feeding trial. Compared with the control basic diet (Group C) and 16 g/kg C-MEA dosage (Group B), the 8 g/kg C-MEA dosage (Group A) increased egg production (average laying rate 69.35%) and follicle development (5~7 Fs, 6~7 LYFs, 11~13 SYFs) mass (p < 0.05). According to RNA-Seq, the ovaries' transcriptome among different dietary groups enriched six key pathways, including neuroactive ligand-receptor interaction, the PPAR signaling pathway, ECM-receptor interaction, focal adhesion, the adherens junction, and the FoxO signaling pathway, as well as 46 candidate key genes. According to 16S-Seq, the microbial diversity was significantly increased in Group A, and the genus abundances of Sphaerochaeta and UCG-004 were significantly changed among different dietary groups (p < 0.05). Supplementation with C-MEA may optimize the cecal microflora and the interactions between the intestinal microflora and the host. The results from combining RNA-Seq and 16S-Seq demonstrated that the relationship between Sphaerochaeta and the hub gene cluster (F2, KNG1, C5, PLG, F2RL1, FABP1, and GCG) is the most prominent. In conclusion, the egg performance of caged laying ducks can be modulated through the microbiota-gut-ovary axis. Our findings provide new insights for improving gut health and reproductive performance of caged laying ducks.

SummaryCadherin 17 (CDH17) has emerged as a promising target for gastrointestinal (GI) cancers, which are often complicated by multidrug resistance (MDR) and recurrence. In this study, we developed 7MW4911, a CDH17-targeted antibody-drug conjugate (ADC) that incorporates a topoisomerase inhibitor MF-6 (Topi MF-6) payload linked via a cleavable linker, designed specifically to address MDR in GI cancers. 7MW4911 exhibited high specificity for CDH17-expressing cancer cells and potent cytotoxicity in vitro. In preclinical models, including patient-derived xenografts (PDXs) with distinct mutations, 7MW4911 achieved tumor growth inhibition ranging from 71% to 99%. Remarkably, 7MW4911 outperformed monomethyl auristatin E (MMAE)-based and Deruxtecan (DXd)-based ADCs in MDR models, highlighting its effectiveness against drug-resistant cancer phenotypes. Additionally, 7MW4911 showed favorable pharmacokinetics and a highest non-severely toxic dose (HNSTD) exceeding 20 mg/kg in cynomolgus monkeys, underscoring its promising safety profile. Together, these findings position 7MW4911 as a promising ADC candidate capable of enhancing therapeutic outcomes in GI cancers.

Abstract Anti-CTLA-4 antibody is considered the “forefront” of immune checkpoint inhibitors as it plays a critical role in preventing CTLA-4 mediated inhibitory signals that downregulate T-cell immune responses, and functioning early at the initial phase of naive T-cell activation. However, CTLA-4 is not a tumor associated antigen and it’s expressed in a variety of normal tissues such as lymph nodes, tonsil and lung, therefore anti-CTLA-4 antibody can trigger severe on-target, off-tumor toxicities and immune-related adverse events (irAEs), substantially restricting its clinical applications and potential. IMD-303 is a novel Tumor MicroEnvironment Activated Antibody (TMEAbody) engineered through chemical conjugation of a legumain-activated chemical linker together with a 20kDa masking group at the variable region. The activating protease, legumain (AEP), is a tumor-specific, acid endopeptidase with tumor site over-expression and a strict specificity for one particular amino acid (Asn), making it a first-in-class, highly specific and pan-solid tumor target in novel drug design. Through screening of TME-activated linkers, glycosylation and masking structures, IMD-303 TMEAbody is inert in circulation as its binding to T cells is blocked in normal tissues, ensuring minimal immunogenicity and systemic toxicities; when entering the Tumor MicroEnvironment (TME), IMD-303 becomes rapidly activated and unmasked by legumain, effectively stimulating CD8+ T-cell proliferation and depleting Treg cells by antibody-dependent cellular cytotoxicity (ADCC). Preclinical pharmacological studies showed that the unmasked IMD-303 exhibited strong binding to CTLA-4, efficiently blocking its interaction with CD80/CD86 in the TME, and high affinity to CD16a, CD32a, and CD64 Fc receptors, enhancing ADCC/ADCP effector functions of Treg depletion locally within the TME. And IMD-303 with masking has greatly improved the safety profile due to the fact that it reduced binding to CTLA-4, CD16a, CD32b (FcγRIIb), and C1q far more than that of CD32a and CD64 in circulation. In animal models, IMD-303 demonstrated strong anti-tumor activities as single agent in multiple syngeneic murine tumor models, and it displayed significant synergistic effects when combined with IMD101 (a TMEA-Cytokine releasing IL-2) in EMT6 tumor model, in which IMD-303 can eliminate the number of Treg cells in tumors that are slightly up-regulated by IMD101. Preclinical toxicology studies showed that the favorable safety profile of IMD-303 allows for continued treatment with repeated dosing, and it’s well-tolerated with a weekly repeated regimen of 200mg/kg in cynomolgus monkeys. All these findings indicate that IMD-303, with its preferential activation within tumors, exhibits superior efficacy and safety performances and has the potential to successfully transform the cold tumor microenvironment which lacks T-cell infiltration and immune responses. Citation Format: Cheng Liu, Yuan Liu, Chengli Ding, Ying He. A novel chemical conjugated anti-CTLA-4 antibody with tumor microenvironment activation [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 6024.

Abstract Purpose: Human Interlukin-2 (hIL-2) targets at malignant tumors, such as renal cell carcinoma and melanoma, and has been on the market for many years. Due to its adverse effects, hIL-2 is limited in clinical use. However, with in-depth studies on the mechanism of action of IL-2 related drugs, IL-2 has been found to have a high potential for use in immunotherapy of oncology, setting off the upsurge of developing improved innovative IL-2 related drugs at home and abroad. The joint application of these drugs and PD-1 in clinical trials for malignant tumors displays a better efficacy and huge market potential. A lot of drug companies have developed IL-2 related drugs and now they are conducting phase I and II clinical trials for metastatic solid tumors and other indications. All of these IL-2 related drugs are designed and developed by half-life extension methods such as molecular mutagenesis and PEGylation, while problems are also existed, for example, a weak-effect and severe side effects. Consequently, according to QbD drug design concept, we have combined molecular mutagenesis with PEGylation to design new molecules and screen out feasible drugs through in vitro and in vivo evaluation experiments, and devoted to developing a novel long-acting IL-2 drug of sustained activation of T cells, offering an alternative choice for current tumor immunotherapy. Method: Facing the defects of these products under development, we carried out molecule design and completed molecular screening of drug candidates through in vitro and in vivo evaluation experiments and pharmacological studies. After that, non-clinical studies were carried out and the comparison with analogous drugs in development was implemented in aspects of efficacy, safety and pharmacy. Result: ZHB114 was screened out as a drug candidate with a better efficacy and fewer side effects. According to the pharmacological studies, ZHB114 was capable of releasing drug activity in a controlled and sustained manner within a safe therapeutic window, thereby enhancing its safety profile. In a number of animal models bearing tumors, ZHB114 has been demonstrated to possess a significantly higher potency than analogous drugs under development. In some models, ZHB114 can elicit complete tumor growth inhibition. The repeated dosing toxicity studies conducted on rats and cynomolgus monkeys have shown that ZHB114 has a wide security window and minimal adverse effects at efficacious doses. It is noteworthy that ZHB114 has been approved by CDE in China, and now it is in the process of preparing for the approval of FDA. Conclusion: Compared with other analogous drugs in development, ZHB114 is more potent and is expected to become a novel long-acting IL-2 agent for tumor immunotherapy, with fewer side effects. Citation Format: Peipei Cao, Biaxue Zhao, Jun Wang, Chenyang Jiang, Yu Zhuang, Bruce Y. Ma. Preclinical study of a novel long-acting receptor-biased rhIL-2 drug with sustained activation of cytotoxic T cells [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 5737.

PurposeBietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive progressive retinal degenerative disease due to mutations in the CYP4V2 gene. Best-corrected visual acuity (BCVA) is a common primary endpoint in clinical trials for retinal diseases, but the natural history of BCVA loss remains unclear because of the heterogeneity of manifestations in BCD patients.MethodsBased on the individual data of untreated BCD patients, a disease progression model was established using the change in BCVA from baseline as an index, and covariates including age of onset, age, duration of disease, baseline BCVA, gender, race (East Asian/non-East Asian), genotype, and family history. Then, based on the final model, the natural disease progression characteristics of BCD were simulated.ResultA total of 14 studies met the inclusion criteria, with a total sample size of 117 cases, including 6 studies (N=80) with East Asian populations and 9 studies (N=37) with non-East Asian populations. The change of BCVA from baseline increased linearly with time, and the disease progression model of BCD was successfully established. BCVA increased by 0.06 logarithm of the minimum angle of resolution (LogMAR) per year in BCD patients. BCVA increased by 0.09 LogMAR per year in patients with BCVA≥0.5LogMAR and disease duration more than 10 years.ConclusionsFor the first time, we successfully established a BCD disease progression model based on the change in BCVA from baseline. The mean visual acuity loss increased linearly with the progression of the disease. A sharper loss of BCVA may be expected in patients with BCVA≥0.5LogMAR and disease duration ≥10 years.