Planegg/Martinsried, May 2, 2024. Medigene AG (Medigene or the “Company”, FSE: MDG1, Prime Standard), an immuno-oncology platform company focusing on the discovery and development of T cell immunotherapies for solid tumors, presented superior T cell receptor engineered T (TCR-T) cell functionality upon combination of optimal affinity 3S (sensitive, specific and safe) TCRs with the PD1-41BB costimulatory switch protein (CSP) at the 7th International Neoantigen Summit held in Amsterdam, Netherlands from April 29 - May 1, 2024..

Planegg/Martinsried，2024年5月2日。Medigene AG（Medigene或“公司”，FSE:MDG1，Prime Standard）是一家专注于实体瘤T细胞免疫疗法的发现和开发的免疫肿瘤学平台公司，在2024年4月29日至5月1日于荷兰阿姆斯特丹举行的第七届国际新抗原峰会上，将最佳亲和力3S（敏感，特异和安全）TCR与PD1-41BB共刺激开关蛋白（CSP）相结合，展示了优异的T细胞受体工程化T（TCR-T）细胞功能。。

The presentation with the title “KRAS Mutation-Specific TCR-T Cells are Empowered for Improved Multi-Functionality & Durability by Inclusion of a Costimulatory Switch Protein” is available on Medigene’s website: https://medigene.com/science/abstracts/

标题为“KRAS突变特异性TCR-T细胞通过包含共刺激开关蛋白来增强多功能性和耐久性”的演示文稿可在Medigene的网站上获得：https://medigene.com/science/abstracts/

Overcoming the immunosuppressive solid tumor microenvironment (TME) stands as a major hurdle for durable TCR-T therapies in patients. The PD-1/PD-L1 axis suppresses T cell activation, proliferation, survival, cytokine secretion and cytotoxicity in a TME with tumor cells that express PD-L1. The Company´s PD1-41BB CSP effectively counters this tumor self-defense mechanism against T cell attack by replacing the inhibitory signaling domain of PD-1 expressed by TCR-T cells with the activating signaling domain of 4-1BB, thereby improving TCR-T cell functionality..

克服免疫抑制性实体瘤微环境（TME）是患者持久TCR-T治疗的主要障碍。PD-1/PD-L1轴抑制TME中表达PD-L1的肿瘤细胞的T细胞活化，增殖，存活，细胞因子分泌和细胞毒性。该公司的PD1-41BB CSP通过将TCR-T细胞表达的PD-1的抑制性信号传导结构域替换为4-1BB的激活信号传导结构域，从而有效地对抗了这种针对T细胞攻击的肿瘤自卫机制，从而改善了TCR-T细胞的功能。。

“Our PD1-41BB CSP, a proprietary component of our End-to-End (E2E) Platform, provides an innovative technology that can be paired with diverse optimal affinity 3S-TCRs that target cancer-testis antigens or neoantigens generated using our high-throughput TCR discovery process,” said Dr. Selwyn Ho, Chief Executive Officer at Medigene.

Medigene首席执行官Selwyn Ho博士说：“我们的PD1-41BB CSP是我们端到端（E2E）平台的专有组件，它提供了一种创新技术，可以与多种最佳亲和力3S TCR配对，这些3S TCR靶向癌症睾丸抗原或使用我们的高通量TCR发现过程产生的新抗原。”。

“Extensive in vitro assessments underscore the significant advantages of armoring and enhancing 3S-TCRs with our PD1-41BB CSP, showcasing the potential to surmount the immunosuppressive TME of solid tumors. This breakthrough combination promises enhanced and persistent efficacy of TCR-T therapies in difficult-to-treat solid tumors.

“广泛的体外评估强调了用我们的PD1-41BB CSP铠装和增强3S TCR的显着优势，展示了克服实体瘤免疫抑制TME的潜力。这种突破性的组合有望增强TCR-T疗法在难治性实体瘤中的持久疗效。

The PD1-41BB CSP can be used not only to improve TCR-T therapies but also holds potential to improve functions in other cell types as well as for application in chimeric antigen receptor T cell therapies.” .

PD1-41BB CSP不仅可用于改善TCR-T疗法，还具有改善其他细胞类型功能以及应用于嵌合抗原受体T细胞疗法的潜力。”。。

“Notably, our innovative TCR discovery method allowed us to identify TCRs possessing distinctive supplementary qualities, demonstrating functionality even in absence of the CD8 co-receptor, normally an important component of immune defense.“

“值得注意的是，我们创新的TCR发现方法使我们能够鉴定具有独特补充品质的TCR，即使在没有CD8共受体（通常是免疫防御的重要组成部分）的情况下也能证明其功能。”

The data presented displayed the exceptional specificity and sensitivity of TCR-T cells co-expressing the PD1-41BB CSP with three different 3S-TCRs that recognize the mKRAS (mutant Kirsten rat sarcoma viral oncogene homologue) G12V neoantigen. This was seen by elevated interferon gamma (IFNγ) secretion, which was solely observed following TCR-T cell stimulation with mKRAS G12V-positive tumor cells but not by stimulation with any tumor or healthy cell type expressing naturally occurring wild-type KRAS protein.

所提供的数据显示了共表达PD1-41BB CSP的TCR-T细胞与识别mKRAS（突变Kirsten大鼠肉瘤病毒癌基因同源物）G12V新抗原的三种不同3S TCR的特异性和敏感性。这可以通过干扰素γ（IFNγ）分泌升高来观察，这仅在用mKRAS G12V阳性肿瘤细胞刺激TCR-T细胞后观察到，而不是通过用表达天然存在的野生型KRAS蛋白的任何肿瘤或健康细胞类型刺激来观察到。

Each of the three 3S TCRs displayed exceptionally high sensitivity for the mKRAS G12V neoantigen, as evidenced by their response to activation by exceedingly low levels of mKRAS-G12V peptide. Coexpression of the PD1-41BB CSP strongly enhanced TCR-T cell functionality and allowed sustained cytotoxicity to be directed against 3D tumor spheroids through multiple rounds of tumor exposure, underscoring the potent anti-cancer activity of the TCR-T cells..

三种3S TCR中的每一种都对mKRAS G12V新抗原表现出极高的敏感性，这可以通过它们对极低水平的mKRAS-G12V肽激活的反应来证明。PD1-41BB CSP的共表达强烈增强了TCR-T细胞的功能，并允许通过多轮肿瘤暴露针对3D肿瘤球体产生持续的细胞毒性，从而强调了TCR-T细胞的有效抗癌活性。。

Finally, all three 3S TCRs exhibited excellent safety profiles. TCR-T cells expressing each of the 3S TCRs, in combination with the PD1-41BB CSP, were not activated to secrete IFNγ nor to mediate killing upon exposure to healthy cells from major tissues or organs, confirming their selective cytotoxicity towards cancer cells without toxicity for healthy tissue..

最后，所有三种3S TCR都表现出优异的安全性。表达每种3S TCR的TCR-T细胞与PD1-41BB CSP结合后，在暴露于主要组织或器官的健康细胞时，不会被激活分泌IFNγ，也不会介导杀伤，从而证实它们对癌细胞的选择性细胞毒性对健康组织没有毒性。。

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About Medigene AG

Medigene AG

Medigene AG (FSE: MDG1) is an immuno-oncology platform company dedicated to developing differentiated T cell therapies for treatment of solid tumors. Its End-to-End Platform is built on multiple proprietary and exclusive technologies that enable the Company to generate optimal T cell receptors against both cancer testis antigens and neoantigens, armor and enhance these T cell receptors engineered (TCR) -T cells to create best-in-class, differentiated TCR-T therapies, and optimize the drug product composition for safety, efficacy and durability.

Medigene AG（FSE:MDG1）是一家免疫肿瘤学平台公司，致力于开发用于治疗实体瘤的分化T细胞疗法。其端到端平台基于多种专有和专有技术，使公司能够产生针对癌症睾丸抗原和新抗原的最佳T细胞受体，保护和增强这些T细胞受体工程（TCR）-T细胞，以创造一流的分化TCR-T疗法，并优化药物产品组成以实现安全性，有效性和耐久性。

The End-to-End Platform provides product candidates for both its own therapeutics pipeline and partnering. Medigene’s lead TCR-T program MDG1015 is expected to receive IND/CTA approval in the second half of 2024. For more information, please visit https://medigene.com/.

端到端平台为其自身的治疗管道和合作提供了候选产品。Medigene的主要TCR-T计划MDG1015预计将于2024年下半年获得IND/CTA批准。有关更多信息，请访问https://medigene.com/.

About Medigene’s TCR-T Cells

关于Medigene的TCR-T细胞

T cells are at the center of Medigene’s therapeutic approaches. Medigene’s immunotherapies help activate the patient’s own defense mechanisms, and harness T cells in the battle against cancer. Medigene’s therapies arm the patient’s own T cells with tumor-specific T cell receptors (TCRs) creating TCR-modified T cells with enhanced potential to detect and efficiently kill cancer cells. .

T细胞是Medigene治疗方法的中心。Medigene的免疫疗法有助于激活患者自身的防御机制，并利用T细胞对抗癌症。Medigene的疗法用肿瘤特异性T细胞受体（TCR）武装患者自己的T细胞，产生TCR修饰的T细胞，具有增强的检测和有效杀死癌细胞的潜力。。。

Medigene’s approach to immunotherapy is designed to overcome the patient’s tolerance of cancer cells and tumor-induced immunosuppression. By activating the patient’s T cells outside the body, genetically modifying them with tumor-specific TCRs and expanding the resultant activated TCR-T cells, patients can rapidly be given large numbers of tumor-specific T cells to fight their cancer..

Medigene的免疫治疗方法旨在克服患者对癌细胞的耐受性和肿瘤诱导的免疫抑制。通过在体外激活患者的T细胞，用肿瘤特异性TCR对其进行基因修饰并扩增所产生的活化TCR-T细胞，可以迅速为患者提供大量肿瘤特异性T细胞来对抗癌症。。

About Medigene’s PD1-41BB Costimulatory Switch Protein

关于Medigene的PD1-41BB共刺激开关蛋白

Checkpoint inhibition via PD-1/PD-L1 pathway:

通过PD-1/PD-L1途径抑制检查点：

Cells of solid tumors are sensitive to killing by activated T cells but can escape this killing activity by producing inhibitory molecules known as ‘checkpoint proteins’, such as the Programmed Death Ligand 1 (PD-L1), on their surface. When this occurs, activated T cells which express PD-1, the natural receptor for PD-L1, are inactivated.

实体瘤细胞对活化的T细胞的杀伤敏感，但可以通过在其表面产生称为“检查点蛋白”的抑制性分子（例如程序性死亡配体1（PD-L1））来逃避这种杀伤活性。当这种情况发生时，表达PD-1（PD-L1的天然受体）的活化T细胞被灭活。

The expression of PD-L1 is an adaptive immune resistance mechanism for tumors that can help them survive and grow..

PD-L1的表达是肿瘤的适应性免疫抵抗机制，可以帮助它们存活和生长。。

The 4-1BB (CD137) costimulatory signaling pathway:

4-1BB（CD137）共刺激信号通路：

Effective T cell immune responses to antigens typically require both a primary antigenic stimulation via the T cell receptor (TCR) and costimulatory signals. The intracellular signaling domains of the 4-1BB protein offer a well-characterized pathway to costimulation and enhanced T cell responses.

对抗原的有效T细胞免疫应答通常需要通过T细胞受体（TCR）进行初级抗原刺激和共刺激信号。4-1BB蛋白的细胞内信号传导结构域为共刺激和增强的T细胞应答提供了良好表征的途径。

Medigene’s PD1-41BB switch receptor turns the tumor’s attempted self-defense mechanism against the tumor by substituting the inhibitory signaling domain of PD-1 with the activating signaling domain of 4-1BB. Therefore, instead of inactivating T cells, the switch receptor delivers an activating signal to TCR-T cells.

Medigene的PD1-41BB开关受体通过将PD-1的抑制性信号传导结构域替换为4-1BB的激活信号传导结构域，从而改变了肿瘤试图针对肿瘤的自卫机制。因此，开关受体不是使T细胞失活，而是向TCR-T细胞传递激活信号。

PD1-41BB-modified TCR-T cells proliferate strongly in the presence of PD-L1-positive tumor cells and kill more tumor cells upon repeated exposure. Additionally, switch receptor signals enable TCR-T cells to function better with low levels of glucose or high levels of TGFß, two conditions characteristic of strongly hostile tumor microenvironments..

PD1-41BB修饰的TCR-T细胞在PD-L1阳性肿瘤细胞存在下强烈增殖，并在反复暴露时杀死更多的肿瘤细胞。此外，开关受体信号使TCR-T细胞能够在低水平葡萄糖或高水平TGFβ的情况下更好地发挥作用，这是强烈敌对的肿瘤微环境的两种特征。。

About KRAS

关于KRAS

KRAS (Kirsten rat sarcoma viral oncogene homologue) belongs to the group of small so-called Guanosine-5′-triphosphate (GTP)-binding proteins, known as RAS-like GTPases. Under physiological conditions KRAS tightly regulates cell proliferation and survival.

KRAS（Kirsten大鼠肉瘤病毒癌基因同源物）属于一组小的所谓鸟苷-5'-三磷酸（GTP）结合蛋白，称为RAS样GTPases。在生理条件下，KRAS严格调节细胞增殖和存活。

In cancer, KRAS is found frequently altered, in a wide variety of often fatal solid cancer types like pancreatic ductal adenocarcinoma, non-small-cell lung cancer, and colorectal cancer. Mutations in the KRAS gene result in the creation of neoantigens which drive uncontrolled proliferation of cancer cells.

在癌症中，KRAS经常被发现在多种致命的实体癌类型中发生改变，如胰腺导管腺癌，非小细胞肺癌和结直肠癌。KRAS基因的突变导致产生新抗原，从而驱动癌细胞不受控制的增殖。

These mutations within the KRAS gene are unique to cancer cells and absent in healthy normal tissue, making KRAS an attractive target for TCR-T therapies. T cell receptor engineered T cell therapies offer a promising approach to targeting these mutations and addressing the challenges posed by solid tumors.

KRAS基因内的这些突变是癌细胞特有的，并且在健康的正常组织中不存在，这使得KRAS成为TCR-T疗法的有吸引力的靶标。T细胞受体工程化T细胞疗法为靶向这些突变和解决实体瘤带来的挑战提供了一种有前途的方法。

Unlike CAR-T cells, which require surface antigens for recognition and may have limitations in target accessibility, TCR-T cells recognize a broader range of targets including intracellular proteins like neoantigens. This unique ability makes TCR-T therapies particularly well-suited for targeting KRAS mutations and other challenging neoantigens..

与CAR-T细胞不同，CAR-T细胞需要表面抗原进行识别，并且可能在靶标可及性方面存在局限性，TCR-T细胞识别更广泛的靶标，包括细胞内蛋白质如新抗原。这种独特的能力使TCR-T疗法特别适合靶向KRAS突变和其他具有挑战性的新抗原。。

This press release contains forward-looking statements representing the opinion of Medigene as of the date of this release. The actual results achieved by Medigene may differ significantly from the forward-looking statements made herein. Medigene is not bound to update any of these forward-looking statements.

截至本新闻稿发布之日，本新闻稿包含代表Medigene观点的前瞻性声明。Medigene取得的实际结果可能与本文所作的前瞻性陈述有很大不同。Medigene不一定会更新这些前瞻性声明。

Medigene® is a registered trademark of Medigene AG. This trademark may be owned or licensed in select locations only..

Medigene®是Medigene AG的注册商标。该商标只能在特定地点拥有或许可。。

Medigene AG

医药产品股份公司

Pamela Keck

帕梅拉·凯克

Phone: +49 89 2000 3333 01

电话：+49 89 2000 3333 01

E-mail: investor@medigene.com

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如果您不再希望收到有关Medigene的任何信息，请通过电子邮件通知我们(investor@medigene.com)。然后，我们将从通讯组列表中删除您的地址。