First in Human Clinical Trial to Evaluate the Safety, Tolerability and Preliminary Efficacy of the Bispecific CD276xCD3 Antibody CC-3 in Patients With Colorectal Cancer

This trial is a first in human (FIH) clinical trial in patients with Colorectal cancer (CRC) after failure of at least three lines of previous therapy aiming to evaluate safety and efficacy of CC-3, a bispecific antibody (bsAb) with CD276xCD3 specificity developed within DKTK. CC-3 binds to CD276 on cancer cells as well as to tumor vessels of CRC, thereby allowing for a dual mode of anti-cancer action. CC-3 was developed in a novel format which not only prolongs serum half-life, but most importantly reduces off-target T cell activation with expected fewer side effects. A similar construct in this format with PSMAxCD3 specificity is presently undergoing clinical evaluation in patients with prostate cancer (NCT04104607), with very favorable safety and preliminary efficacy. The optimized format that CC-3 shares with its PSMAxCD3 "sister molecule" allows for application of effective bsAb doses with expected high anticancer activity. The clinical trial comprises two phases: The first phase is a dose-escalation part to evaluate the maximally tolerated dose (MTD) of CC-3. This is followed by a dose-expansion part to defined the recommended phase II dose. A translational research program comprising, among others, analysis of CC-3 half-life and the induced immune response will serve to better define the mode of action of CC-3.

开始日期2024-01-12

申办/合作机构

German Cancer Research Center

100 项与 CC-3 相关的临床结果

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100 项与 CC-3 相关的转化医学

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100 项与 CC-3 相关的专利（医药）

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项与 CC-3 相关的文献（医药）

2024-10-01·Plant Disease

Evaluation of Ergot Resistance in Hard Red Spring Wheat in North Dakota

Article

作者: Green, Andrew ; Lux, LeAnn ; Friskop, Andrew ; Kilber, Harlee ; Hansen, Bryan ; Dusek, Gabriel ; Scherer, Jessica

Higher levels of ergot (Claviceps purpurea [Fr.] Tul.) were reported in North Dakota hard red spring wheat (HRSW) in 2018, leading to questions pertaining to management and cultivar resistance. To better understand pathogen and HRSW cultivar responses, greenhouse experiments were conducted from 2020 to 2021 to evaluate the aggressiveness of nine C. purpurea isolates and ergot resistance in 21 HRSW cultivars. Results from the aggressiveness assay indicated significant cultivar-by-isolate interactions for the total weight of sclerotia produced and ergot incidence. Mean data across all cultivars by isolate combinations suggested isolates CC-3 and IA-Tim were the most aggressive, and these were subsequently used in ergot resistance experiments. Results from ergot resistance screening indicated that none of the HRSW cultivars were immune to C. purpurea because all cultivars produced sclerotia. However, differences in ergot incidence, kernel incidence, aborted kernel incidence, total sclerotia weight, sclerotia length, and sclerotia width occurred among cultivars. Both ‘ND-Frohberg’ and ‘TCG-Spitfire’ had the lowest ergot incidence values and were among the lowest in total sclerotia weight. ‘Waldron’ and ‘LCS-Trigger’ had the highest ergot incidence and the highest total sclerotia weight. Given that most concerns with ergot occur postharvest, we suggest two categories to describe ergot resistance: host resistance (fate of inoculation for a stigma) and logistical resistance (size characteristics of a sclerotium that influence its ability to remain with a seed lot after harvest and cleaning). This research provides a strong foundation for our understanding of HRSW resistance to ergot that will influence variety decisions in ergot-prone areas in North Dakota.

2023-05-01·Investigative and clinical urology

Therapeutic responses to chemotherapy or immunotherapy by molecular subtype in bladder cancer patients: A meta-analysis and systematic review.

Review

作者: Yuan, Xiaoyu ; Ge, Chengguo ; Wang, Shunde ; Zhang, Junyong ; Zhao, Jiaming ; Zheng, Baishu ; Shen, Zhongjie

To systematically evaluate the differences in therapeutic response to chemotherapy or immunotherapy between different molecular subtypes of bladder cancer (BC). A comprehensive literature search was performed up to December 2021. Consensus clusters 1 (CC1), CC2 and CC3 molecular subtypes were used to perform meta-analysis. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the therapeutic response by fix-effect modeling. Eight studies involving 1,463 patients were included. For immunotherapy, CC3 showed the highest response rate (CC1 vs. CC3: OR=0.52, 95% CI=0.34-0.78, p=0.002; CC2 vs. CC3: OR=0.42, 95% CI=0.28-0.62, p<0.001), which was mainly reflected in the highest response rate to atezolizumab (CC1 vs. CC3: OR=0.47, 95% CI=0.29-0.75, p=0.002; CC2 vs. CC3: OR=0.38, 95% CI=0.24-0.59, p<0.001). For chemotherapy, CC3 had the lowest response rate to the overall chemotherapy (CC1 vs. CC3: OR=2.05, 95% CI=1.23-3.41, p=0.006; CC2 vs. CC3: OR=2.48, 95% CI=1.50-4.10, p<0.001). Compared with CC2, CC3 responded poorly to both neo-adjuvant chemotherapy (NAC) (OR=1.93, 95% CI=1.09-3.41, p=0.020) and chemoradiation therapy (CRT) (OR=6.07, 95% CI=1.87-19.71, p<0.001). Compared with CC1, CC3 only showed a poorer response to CRT (OR=4.53, 95% CI=1.26-16.27, p=0.020), and no difference in NAC. Our study suggested that molecular classifications are important predictors of cancer treatment outcomes of BC patients and could identify subgroup patients who are most likely to benefit from specific cancer treatments.

2023-04-01·Molecular Therapy

An optimized IgG-based B7-H3xCD3 bispecific antibody for treatment of gastrointestinal cancers

Article

作者: Hagelstein, Ilona ; Heitmann, Jonas S ; Chashchina, Anna ; Hoerner, Sebastian ; Jung, Gundram ; Salih, Helmut R ; Mueller, Stefanie ; Manz, Timo ; Lutz, Martina ; Klimovich, Boris ; Zekri, Latifa ; Pfluegler, Martin ; Prakash, Nisha ; Engel, Monika

T cell-based immunotherapy has revolutionized oncological treatment. However, many patients do not respond to treatment, and long-term remissions remain rare, particularly in gastrointestinal cancers like colorectal cancer (CRC). B7-H3 is overexpressed in multiple cancer entities including CRC on both tumor cells and tumor vasculature, the latter facilitating influx of effector cells into the tumor site upon therapeutic targeting. We generated a panel of T cell-recruiting B7-H3xCD3 bispecific antibodies (bsAbs) and show that targeting a membrane-proximal B7-H3 epitope allows for a 100-fold reduction of CD3 affinity. In vitro, our lead compound CC-3 showed superior tumor cell killing, T cell activation, proliferation, and memory formation, whereas undesired cytokine release was reduced. In vivo, CC-3 mediated potent antitumor activity in three independent models using immunocompromised mice adoptively transferred with human effector cells with regard to prevention of lung metastasis and flank tumor growth as well as elimination of large established tumors. Thus, fine-tuning of both target and CD3 affinities as well as binding epitopes allowed for the generation of a B7-H3xCD3 bsAbs with promising therapeutic activity. CC-3 is presently undergoing good manufacturing practice (GMP) production to enable evaluation in a clinical "first-in-human" study in CRC.

100 项与 CC-3 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
结直肠癌	临床1期	德国	German Cancer Research Center	2024-01-12
女性生殖器官肿瘤	临床前	德国	Eberhard Karls Universität Tübingen	2024-04-10
HER2 阴性乳腺癌	药物发现	德国	Eberhard Karls Universität Tübingen	2023-11-02