MICA

Company will initiate Phase 1 study of CLN-619 for relapsed or refractory multiple myeloma, first MICA/B antibody clinical study in hematologic malignancies Follows ongoing clinical study of CLN-619 alone and in combination with pembrolizumab in solid tumors, with anticipated updated clinical data in Q2 2024 March 01, 2024 -- Cullinan Oncology, Inc. (Nasdaq: CGEM), a biopharmaceutical company focused on modality-agnostic targeted oncology therapies, today announced the U.S. Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application for CLN-619 in relapsed/refractory multiple myeloma. CLN-619 is a potential first-in-class humanized IgG1 monoclonal antibody that binds to stress-induced ligands, MICA and MICB, which are expressed on a wide variety of solid tumors and hematologic malignancies. The company will commence a Phase 1 dose-escalation and dose-expansion trial of CLN-619. “Multiple myeloma remains incurable, and most patients experience sequential relapses. The response to treatment is typically shorter with each relapse, so novel treatments are still needed,” said Jeffrey Jones, MD, MPH, MBA, Chief Medical Officer, Cullinan Oncology. “Multiple myeloma is another example of a malignancy where MICA/B shedding from tumor cells allows for immune evasion. As we shared at SITC 2023, CLN-619 restores MICA/B expression on tumor cells, enabling immune recognition. This Phase 1 trial will assess CLN-619 in patients with multiple myeloma, and, given the safety profile shown to date for CLN-619, we believe there is an opportunity to combine the monoclonal antibody with multiple standard therapies. With clinical studies in both solid tumors and hematologic malignancies, we look forward to assessing the full potential of CLN-619 to address multiple areas of unmet clinical need.” CLN-619 is a potential first-in-class humanized IgG1 monoclonal antibody that binds to the stress-induced ligands MICA and MICB, which are expressed on a wide variety of solid tumors and hematologic malignancies. Engagement of MICA/B by the activating receptor NKG2D, present on both cytotoxic innate and adaptive immune cells, results in target cell lysis. However, tumor cells can shed MICA/B via proteases they release into the tumor microenvironment, resulting in evasion of immune-mediated destruction. CLN-619 functions by restoring MICA/B expression on the surface of tumor cells, enhancing the interaction between MICA and NKG2D, and inducing antibody-dependent cellular toxicity (ADCC), together promoting anti-tumor activity via multiple immune-mediated mechanisms. CLN-619 is being studied in an ongoing Phase 1 clinical trial (NCT05117476) both as a monotherapy and in combination with pembrolizumab in patients with solid tumors. The study design allows dose level extensions as well as expansion in tumor-specific cohorts. CLN-619 will also be studied in a Phase 1 clinical trial in patients with relapsed/refractory multiple myeloma. Cullinan Oncology, Inc. (Nasdaq: CGEM) is a biopharmaceutical company dedicated to creating new standards of care for patients with cancer. We innovate without borders to find the most promising clinic-ready cancer therapies, whether from our own discovery efforts or through exceptional engagement with our academic and industry partners. Anchored in a deep understanding of immuno-oncology and translational cancer medicine, we leverage our scientific excellence in small molecules and biologics to create differentiated ideas, identify unique targets, and select the optimal modality to develop transformative therapeutics across cancer indications. Powered by our novel research model, we push conventional boundaries from candidate selection to cancer therapeutic, applying rigorous early experimentation to fast-track only the most promising assets to the clinic and ultimately commercialization. As a result, our diversified pipeline is strategically built with assets that activate the immune system or inhibit key oncogenic drivers across a wide range of modalities, each with the potential to be the best or first in their class. Our people possess deep scientific expertise, seek innovation openly, and exercise creativity and urgency to deliver on our promise to bring new therapeutic solutions to patients with cancer. Learn more about our Company at www.cullinanoncology.com, and follow us on LinkedIn and Twitter. The content above comes from the network. if any infringement, please contact us to modify.

近年来，除了备受瞩目的CAR-T疗法外，“CAR-NK细胞”这一后起之秀也逐渐进入人们的视野，兼具先天免疫特性的自然杀伤（NK）细胞，经CAR工程改造后，仿佛自带“导航头”，不仅杀伤力倍增，而且可能更安全、更便宜，在血液系统恶性肿瘤和难治性实体瘤领域，具有广阔的应用前景！ 搭载“导航头”的CAR-NK细胞，杀伤力倍增 01 何谓CAR-NK细胞 “CAR-NK细胞”即” 嵌合抗原受体-NK （chimericantigenreceptor-NK，CAR-NK）细胞”，是从健康供体和患者中， 分离同种异体和自体NK细胞 ，然后仿造CAR-T细胞的设计， 对NK细胞进行CAR工程改造 ， 相当于给NK细胞安装上“导弹头” ，使其在 保留NK细胞原有功能 的前提下，又能 将目标精准锁定在特定的抗原蛋白 上，从而提高抗肿瘤的效果。 图1 CAR-NK介导的细胞疗法 ▲图源“PMC”，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除 02 CAR-NK与CAR-T疗法的优劣对比 与CAR-T疗法相比，CAR-NK细胞保留了通过 天然受体识别、靶向异常细胞 的内在能力，更好的避免了 肿瘤免疫逃逸 的发生，而且 副作用更小 ，作为“现货型”细胞产品， 价格更低廉、等待时间更短、实用性更高 ，具体区别详见下表： ▲数据源自“Am J Cancer Res” 想寻求NK细胞疗法或CAR-NK细胞疗法及其他国内外治疗新技术帮助，且经济条件允许的患者，可将病历、近期病理结果等，提交至全球肿瘤医生网医学部进行初步评估！ CAR-NK疗法，治疗血液肿瘤的“新武器” 01 NKX101：治疗急性髓系白血病，CR/CRi率达67% 急性髓系白血病（AML）是成人中最常见的白血病类型，其治疗选择有限、预后较差，高发病率和死亡率主要归因于复发和化疗耐药。近年研究显示， CAR-NK细胞可作为免疫治疗的“新武器”，用于治疗AML等多种血液恶性肿瘤 。 NKX101 是一种现成的癌症免疫治疗候选药物，源自健康供体的NK细胞，经过改造后，可 表达NKG2D配体导向的嵌合抗原受体(CAR) ，以增强对癌细胞的杀伤力。NKX101的1期试验，选择复发或难治性（r/r）AML患者入组，在进行淋巴细胞清除术后，接受NKX101治疗。 在接受Flu/Ara-C（氟达拉滨对阿糖胞苷）淋巴细胞清除的r/rAML患者中， 6例患者中有4例达到CR/CRi（67%CR/CRi率），有3例达到血液学恢复的完全缓解（50%CR） 。此外，在4例完全缓解的患者中，有2例MRD（可测量残留病灶）呈阴性，提示无病生存率增加、复发风险降低。 02 NKX019：B细胞恶性肿瘤新“克星”，完全缓解率高达70% NKX019是一种 冷冻保存的同种异体CAR-NK细胞疗法，可表达针对CD19的人源化CAR ，以增强其内在抗肿瘤活性，用于治疗B细胞恶性肿瘤。 2023年欧洲血液学协会（EHA）大会上，公布了 NKX019的1期临床试验的初步数据（NCT05020678） 。该研究共纳入19例复发或难治性（r/r）B细胞恶性肿瘤患者，其中14例患有非霍奇金淋巴瘤[大B细胞淋巴瘤(LBCL)、 滤泡性淋巴瘤(FL)、套细胞淋巴瘤(MCL)、边缘区淋巴瘤(MZL)]，5例患有白血病[慢性淋巴细胞白血病（CLL）、急性淋巴细胞白血病（ALL）]。这些患者的中位年龄为59岁（21~82岁），之前都接受过至少2种治疗，ECOG体能状态为0或1。在治疗过程中，患者需要先接受淋巴细胞清除术（氟达拉滨+环磷酰胺）；之后再接受NKX019治疗。 结果显示，在可评估的患者（n=10）中， 总体缓解率为80%，其中完全缓解（CR）率达70%；大B细胞淋巴瘤（LBCL）患者的CR率为50% 。这项突破性的研究表明， NKX019具有可控的安全性，在多种NHL组织学中均具有活性 。 ▲图源“WILEYOnline Library”，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除 CAR-NK疗法剑指多款实体瘤，未来可期 目前，多项研究证实了CAR-NK细胞，在多款实体瘤治疗方面的可行性，如 胰腺癌、卵巢癌、直结肠癌、肝细胞癌、肝细胞癌、乳腺癌、头颈鳞状细胞癌 等。 01 NKG2DCAR-NK细胞，治疗结直肠癌安全可行 2020年广州医科大学的一篇硕士论文中，提到了“ 采用靶向NKG2D的CAR-NK细胞疗法，治疗结直肠癌 ”的临床研究结果。 在该研究中，共入组3例转移性结直肠癌患者，通过局部输注的方式，给予NKG2DpCAR-NK细胞治疗。前两例患者经腹腔输注低剂量CAR-NK细胞后，可观察到 腹水生成量减慢，且腹水样本中肿瘤细胞数量急剧减少 。第3例患者发生了肝脏转移，采用腹腔内灌注+超声引导下瘤内经皮注射方式，给予CAR-NK细胞治疗后， 多普勒超声可见肝脏肿瘤快速缩小 ；正电子发射断层扫描（PET-CT）提示，治疗后的肝脏病灶为完全代谢反应，详见下图。此外，这3例患者在治疗过程中，均未出现3级或以上的不良事件。 图2 CAR-NK细胞治疗后，肝转移病灶PEC-CT对比图 综上，本研究结果初步提示， NKG2D mRNA CAR-NK细胞治疗转移性结直肠癌的安全性和可行性 ，为难治性结直肠癌患者提供了一种新型的免疫治疗策略。 02 国内首个“即用型”CAR-NK疗法临床实验获批——针对卵巢癌 ▲截图源自“NMPA官网” 2021年11月，国家药监局药品审评中心通过了一款“ 晚期上皮性卵巢癌治疗的靶向间皮素（MSLN）嵌合抗原受体NK细胞（CAR-NK）注射液 ”的临床试验申请。 据全球肿瘤医学部小编获悉，此款产品是我国自主研发的，国内首个IND获批的“现货型”CAR-NK产品，可进行标准化批量生产，临床普及性较高，有助于减少治疗成本、提高卵巢癌的治疗效果，改善患者的生活质量，标志着我国实体瘤治疗进入了全新的篇章。 03 我国研发NK010注射液，卵巢癌病灶缩小60% 在2023年6月美国临床肿瘤学会（ASCO）年会上，公布了我国研发的非基因修饰外周血来源 NK010注射液，在治疗铂不耐受或铂耐药的晚期难治性卵巢癌、难治/复发性急性髓细胞白血病（AML） 方面的临床试验数据。 结果显示，低剂量组和1例中剂量患者，在治疗两个疗程后，疾病评估稳定。其中，低剂量组患者后续使用同一剂量继续治疗，在接受治疗第3个疗程后，达到部分缓解。 在持续接受治疗的患者中，最佳疗效为病灶缩小60% 。 04 FT536新药IND获FDA批准——剑指多种实体瘤 美国FDA于2022年1月，批准了 FT536（一项创新CAR-NK疗法）的新药临床研究（IND）申请 。 FT536是一款 经多重工程修饰、诱导多能干细胞（iPSC）衍生的“即用型”CAR-NK细胞疗法 ，可表达主要组织相容性复合体（MHC）相关蛋白A和B（MICA/MICB），MICA和MICB二者属应激蛋白，在许多实体瘤中高水平表达，有望成为广泛实体瘤治疗中的理想靶标。 FT536的I期临床试验主要针对 乳腺癌、卵巢癌、胰腺癌、胃癌、晚期非小细胞肺癌、结直肠癌、头颈癌 等多种实体瘤。 小编有话说 CAR工程的出现，引领了细胞治疗领域的变革。其中，CAR-T奠定了免疫疗法的基础；而CAR-NK细胞的出现，为肿瘤治疗带来了新的突破，并扩展了其在转移性实体瘤和血液恶性肿瘤等领域的应用前景。小编也期望未来会有更多技术与CAR工程结合，以增强免疫效应细胞功能，造福更多的恶性肿瘤患者！ 参考资料 [1]Zhang L,et al.CAR-NK cells for acute myeloid leukemia immunotherapy: past, present and future[J]. American Journal of Cancer Research,2023,13(11): 5559. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10695781/ [2]https://ir.nkartatx.com/news-releases/news-release-details/nkarta-updates-clinical-progress-car-nk-cell-therapy-nkx101/ [3]https://onlinelibrary.wiley.com/doi/full/10.1002/hon.3164_389

PASADENA, CA, USA I November 03, 2023 I Xencor, Inc. (NASDAQ: XNCR), a clinical-stage biopharmaceutical company developing engineered antibodies and cytokines for the treatment of cancer and autoimmune diseases, today presented data from multiple preclinical-stage XmAb ® programs at the 38th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) in San Diego. “Xencor aims to stay on the leading edge of molecular engineering, using and improving upon our XmAb technologies to create molecules with enhanced functionality or new therapeutic mechanisms. At SITC, we are presenting new preclinical data from two research-stage programs—engineered, decoy-resistant IL18-Fc fusions and our multi-valent NK cell engagers targeted to MICA and MICB, which are tumor antigens upregulated in the tumor microenvironment,” said John Desjarlais, Ph.D., executive vice president and chief scientific officer at Xencor. “Later this year, we expect to submit an investigational new drug application for XmAb541, an XmAb 2+1 format CLDN6 x CD3 bispecific antibody that we are developing for patients with ovarian cancer and other tumor types. We are also developing additional CD3 and CD28 T cell engaging bispecific antibodies against solid tumor targets.” Posters will be available in the poster hall and virtually to registrants of the SITC Annual Meeting. In the poster hall, odd-numbered posters will be displayed on Friday, November 3, and even-numbered posters will be displayed on Saturday, November 4. Xencor’s posters will be archived under "Events & Presentations" in the Investors section of the Company's website located at www.xencor.com . Clinical Trials in Progress Abstract 764, “A Phase 1, first-in-human (FIH), open-label, dose-finding and expansion study of XmAb808, a B7H3 x CD28 bispecific antibody, in combination with pembrolizumab in patients with advanced solid tumors” Xencor is conducting a Phase 1 study of XmAb808 in patients with advanced solid tumors. XmAb808 is a tumor-selective, co-stimulatory XmAb 2+1 bispecific antibody designed to bind to the broadly expressed tumor antigen B7-H3 and selectively to the CD28 T-cell co-receptor only when bound to tumor cells, which was demonstrated in vitro . Strong potentiation of checkpoint and CD3 cytotoxic activity was also observed in vivo . XmAb808 is a wholly owned Xencor program. The clinical trials in progress poster reviews the design of XmAb808 and the rationale of using CD28 bispecific antibodies to expand the utility of checkpoint blockade and CD3 T cell engagers. The poster also provides study objectives, key eligibility criteria and study schema. Preclinical Programs Abstract 1060, “Optimally engineered IL18-Fc fusion proteins balance potency and pharmacokinetics to promote strong anti-tumor activity” IL-18 is a proinflammatory cytokine that modulates both the innate and adaptive immune responses. Preclinical studies of IL-18 have demonstrated its anti-tumor activity, including synergy with immune checkpoint inhibitors and CAR-T therapies. In contrast with other potent cytokines, IL-18 has been well tolerated in clinical trials but demonstrated a lack of efficacy despite heavy dosing. IL-18 induces a negative feedback loop with its high affinity natural inhibitor, IL18BP, which was upregulated in early phase clinical studies and may have limited IL-18’s clinical performance. Xencor engineered stabilized, potency-modulated IL-18 cytokines fused to an XmAb heterodimeric Fc domain with Xtend™ Fc technology for longer half-life (IL18-Fc). In addition, Xencor engineered bispecific IL18-Fc cytokines targeted to PD-1, a checkpoint receptor on T cells. Importantly, these molecules were engineered to avoid binding IL18BP. Xencor’s IL18-Fc fusions and PD1 x IL18-Fc bispecific inhibited tumor growth in a dose- and potency-dependent manner, outperforming a wild-type IL18-Fc fusion, in vivo . Further preclinical studies of the engineered IL18-Fc fusions demonstrated pharmacodynamic profiles similar to wild-type IL18-Fc. Notably, a set of surviving tumor-engrafted mice, which had previously received engineered IL18-Fc fusions, had no tumor growth upon rechallenge. Abstract 1193, “Synergistic targeting of multiple activating pathways with Natural Killer cell Engagers” Xencor’s XmAb natural killer cell engagers (NKEs) are multifunctional antibodies that target multiple activating receptors on the surface of NK cells and bind to tumor-associated antigens. MICA and MICB (MICA/B) are stress-induced tumor antigens expressed in a range of cancers. MICA/B antigens are recognized by NKG2D, an activating receptor on NK and CD8+ T cells. While membrane-bound, MICA/B is immuno-stimulatory; however, the cleaved and soluble form, found in the tumor microenvironment, prevents NKG2D from recognizing tumor cells. Xencor engineered anti-MICA/B antibodies with enhanced effector function in order to block the cleavage of MICA/B antigens and promote NK cell engagement. These antibodies increased MICA/B membrane surface density and led to tumor cell killing with MICA/B binding to NKG2D on immune cells. To enhance the anti-tumor activity, Xencor engineered multi-specific NK cell-engaging antibodies that simultaneously target MICA/B antigens and an orthogonal activating receptor on NK cells, NKp46. These multi-specific NK cell-engaging antibodies demonstrated enhanced functional activity compared to the antibodies targeting only MICA/B. About Xencor Xencor is a clinical-stage biopharmaceutical company developing engineered antibodies and cytokines for the treatment of patients with cancer and autoimmune diseases. More than 20 candidates engineered with Xencor's XmAb ® technology are in clinical development, and three XmAb medicines are marketed by partners. Xencor's XmAb engineering technology enables small changes to a protein's structure that result in new mechanisms of therapeutic action. For more information, please visit www.xencor.com . SOURCE: Xencor