BCMA

Results from the dose-escalation portion of the Phase 1 clinical study of ISB 2001 in patients with heavily pretreated multiple myeloma to be presented at the 2025 ASCO Annual Meeting NEW YORK, May 5, 2025 /PRNewswire/ -- IGI, a global, fully integrated clinical-stage biotechnology company focused on developing multispecifics™ in oncology, today announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for ISB 2001. This important designation was granted for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least three prior lines of therapy including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. ISB 2001 is an investigational trispecific antibody therapeutic that targets BCMA and CD38 on myeloma cells and CD3 on T cells. ISB 2001 is currently being evaluated in a Phase 1 dose-expansion study. "A growing number of patients with multiple myeloma have been heavily pretreated, have exhausted currently approved therapies, and continue to face disease progression," said Cyril Konto, M.D., President and CEO of IGI. "At IGI, we have long recognized the urgent need for novel treatment options – particularly for patients who have already received first-generation bispecifics or CAR T-cell therapies. Our trispecific candidate is designed to enhance tumor targeting while reducing on-target, off-tumor toxicity. We are honored to receive this Fast Track designation and look forward to working closely with the FDA to advance our Multispecific™ T-cell engager, with the goal of delivering a first-in-class therapy for patients with relapsed or refractory multiple myeloma." IGI recently completed the dose-escalation portion of its Phase 1 clinical study in patients with heavily pretreated multiple myeloma. Initial study results, presented in an oral session at the American Society of Hematology (ASH) Annual Meeting in December 2024, demonstrated a high overall response rate (ORR) with durable responses and a favorable safety profile. Complete results from the dose-escalation portion will be presented in a rapid oral session at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting on Monday, June 2, 2025. The FDA's Fast Track designation is designed to enable the development and expedite the review of drugs that treat serious conditions and address unmet medical needs, with the ultimate goal of getting important new drugs to patients earlier. A drug that receives Fast Track designation may be eligible for more frequent meetings and communications with the FDA and rolling review of any application for marketing approval. A drug receiving Fast Track designation also may be eligible for Priority Review if relevant criteria are met. ISB 2001 was previously granted Orphan Drug Designation by the FDA in July 2023. ASCO Rapid Oral Presentation Details: Session title: Phase 1, first-in-human study of ISB 2001: A BCMAxCD38xCD3-targeting trispecific antibody for patients with relapsed/refractory multiple myeloma (RRMM)—Dose escalation results. (Abstract # 7514) Session Name: Hematologic Malignancies—Plasma Cell Dyscrasia Date & Time: June 2, 2025, 8 AM – 9:30 AM CDT About ISB 2001 and Relapsed/Refractory Multiple Myeloma ISB 2001 is a first-in-class trispecific T-cell engager that targets BCMA and CD38 on myeloma cells and CD3 on T cells. Developed using IGI's proprietary BEAT® protein platform, ISB 2001 was engineered with two distinct binders against myeloma-associated antigens to enhance avidity, even at low target expression levels, while aiming to improve safety over first-generation bispecific antibodies. The dose-expansion portion of the ongoing Phase 1 trial in patients with RRMM (NCT05862012) is currently enrolling patients across 9 sites in the United States and Australia. Nearly all patients with relapsed or refractory multiple myeloma (RRMM) ultimately experience disease progression. With no cure currently available and limited treatment options once approved therapies are exhausted, there remains a significant unmet need. IGI is developing ISB 2001 to address this gap, specifically for patients who have previously received T-cell–directed therapies, including CAR T-cell treatments and bispecific antibodies. About IGI IGI is a global, fully integrated clinical-stage biotechnology company focused on developing innovative biologics in oncology. Headquartered in New York, NY, IGI is advancing a robust pipeline of novel, first-in-class multispecifics™ aimed at addressing complex diseases and treating patients holistically. Powered by its proprietary BEAT technology platform, IGI is committed to delivering breakthrough, curative therapies to improve and extend the lives of patients battling hematological malignancies and solid tumors. For more information, visit . SOURCE Ichnos Glenmark Innovation WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

The first shards of human data on in vivo CAR-T cell therapy look promising, based on recent separate reports from two biotech companies’ academic-led studies in China. Last week, a Chinese startup called Genocury became the second company to share initial clinical data on a CAR-T treatment that doesn’t require a patient’s cells to be extracted from their body. Genocury said that an advanced large B cell lymphoma patient went into complete remission after one month of in vivo CAR-T therapy, and has remained in remission for over three months. Notably, the in vivo CAR-T therapy does not require lymphodepletion, a course of chemotherapy that conventional CAR-T therapies require before treatment and that comes with toxicities. “This is good news for the field and demonstrates the increasing momentum around in vivo CAR-T approaches,” said University of Pennsylvania CAR-T pioneer Bruce Levine, who isn’t involved in Genocury’s studies but is a scientific founder of another in vivo CAR-T company called Capstan. Last week’s results follow Belgian startup EsoBiotec’s announcement in January that a multiple myeloma patient who received the lowest dose of its in vivo CAR-T therapy had no detectable cancer cells in their bone marrow at one month, without any significant adverse events during treatment. That patient also did not receive prior lymphodepletion. The data from both companies come from investigator-initiated studies in China, which biotech startups have been leveraging more frequently to quickly generate early clinical data on their experimental treatments. EsoBiotec is working with Pregene Biopharma which, like Genocury, is based in Shenzhen. In March, AstraZeneca announced plans to acquire EsoBiotec for $425 million, plus additional payments. At least five groups have begun clinical trials for in vivo CAR cell therapies. Aside from EsoBiotec and Genocury, Myeloid Therapeutics, Interius BioTherapeutics and Umoja Biopharma are all studying experimental in vivo cell therapies in patients. In conventional CAR-T therapy, a patient’s cells are extracted, engineered, and then reinfused — a complex, expensive process that can take weeks to months. The therapy, while transformative for certain blood cancers, comes with safety risks from the lymphodepletion before treatment and immune overreaction (cytokine release syndrome and ICANS) afterwards. And so far, comparatively less complex “off-the-shelf” treatments using donor cells have yet to take off. Makers of in vivo cell therapy hope that their treatments can become a different kind of “off-the-shelf” option. Their therapies deliver genetic material to turn the patient’s immune cells into cancer-fighting ones directly in the body. The companies are using different technologies to deliver their treatments and are also going after a range of diseases. The delivery technologies fall into two camps: viral and non-viral. Researchers have more concerns around the potential risks of a virus-based therapy, including of secondary cancer, but it’s an older and more proven approach. Non-viral delivery is newer and more challenging, and fewer companies have reached clinical studies. It is unclear based on Genocury’s disclosures whether it is using a viral or non-viral approach. A photo on its website mentions both viral and non-viral methods, and the company could not be reached for comment. EsoBiotec is developing a lentiviral-based cell therapy that goes after BCMA, a well-known target for multiple myeloma. Interius, which expects to report clinical data later this year, and Umoja are likewise studying lentiviral-based therapies. Umoja, like Genocury, is developing a CD19-targeted CAR-T therapy for blood cancer, and it plans to study the treatment in autoimmune disease as well. AbbVie has an option to license that therapy, and in January the startup raised $100 million to jumpstart its clinical studies. Interius’ therapy targets another immune cell protein called CD20, and it’s studying its B cell cancer therapy in both Australia and Germany. The Philadelphia biotech’s therapy is meant to make both ​​CAR-T and NK cells directly in the body. On the other hand, Sid Mukherjee’s startup Myeloid is using mRNA delivered non-virally. It uses fatty acid envelopes called lipid nanoparticles — similar to what’s used in the Covid vaccines. However, as its name suggests, it’s targeting a type of immune cell called myeloid cells. It has two programs in the clinic going after solid tumors — an area of cancer that conventional CAR-T therapies have yet to crack.

CAR-T 细胞疗法在多种血液系统恶性肿瘤的治疗中显示出巨大的希望，包括非霍奇金淋巴瘤 (NHL) 和急性淋巴细胞白血病 (ALL)，但原发性难治性或复发性疾病是一个相对常见的现象。失败的原因很复杂，可能包括 T 细胞功能障碍、肿瘤微环境 (TME) 引起的免疫抑制、高肿瘤负荷和抗原逃逸等。其中抗原逃逸 (靶抗原表达缺失或下调) 是侵袭性 B 细胞恶性肿瘤患者耐药的主要机制，其机制也有多种，包括选择预先存在的抗原阴性克隆、抗原表达减少、获得突变、剪接位点变异、谱系转换介导的抗原丢失 (通常发生于有特定基因组异常 [如 KMT2A 重排] 的患者) 和表面抗原呈递失败。当然，这些机制通常是同时发生的。对于抗原逃逸，理论上可以通过给予靶向多抗原的多靶点 CAR-T 来克服这一机制，临床前数据也显示双靶点 CAR-T 细胞疗效优于单靶点 CAR-T 细胞，这些为具有两种或两种以上抗原特异性的产品 (如 CD19 和 CD20、CD19 和 CD22、CD19 和 BCMA 等) 的开发铺平了道路。双靶点 CAR-T 细胞的治疗策略主要有如下四种：• 单靶点 CAR-T 细胞的联合给药：包括生产两种单独的 CAR-T 细胞，并在短时间内给药。• 共转导 CAR-T 细胞：将 T 细胞共转导两个单独的病毒载体，每个载体编码不同的 CAR。需要生产一次 CAR-T 细胞，但包含两个单独的载体。• 双顺反子 CAR-T 细胞：使用编码两种不同 CAR 的单一载体生产一种 CAR-T 细胞。• 串联或环状 CAR-T 细胞：使用单一载体生产一种 CAR-T 细胞，该载体可编码具有两个不同单链可变片段 (scFv) 的单个 CAR。串联结构由一个 scFv 的 VL-VH 序列与第二个 scFv 的 VL-VH 序列直接连接组成（经典串联），而在环结构中，一个 scFv 的 VL 和 VH 序列被另一个 scFv 的 VL-VH 分离。相关数据见下表，原文有部分研究的详细介绍（10.1111/ bjh.19348）。事实上，四种策略均有自身的优缺点，具体如下。单靶点 CAR-T 细胞的联合给药合并或组合给予两种不同的 CAR-T 细胞是实现双靶点的最简单选择，特别是当两种 CAR-T 细胞都有成熟数据时，但它也是最昂贵的策略，因为每例患者需要两个完整且独立的制造流程。两种药物制成后，可混合使用并一起给药 (一次输注）或单独给药（两次输注）。此外，两次给药可以几乎连续发生 (即同一天或第二天），也可以相隔几个月。如果两次给药间隔太远，可能需要重复进行清淋化疗。共转导 CAR-T 细胞共转导需要使用两种不同的病毒载体进行单细胞制造过程，虽然操作相对简单，但由于使用的是两种载体而非一种载体，因此比传统的 CAR-T 细胞制造成本更高，并且最终产品存在一定程度的异质性。此策略的关键特征在于，所得细胞产物含有以下四种细胞群的混合物：(i) 具有一种抗原特异性的细胞；(ii) 具有另一抗原特异性的细胞；(iii) 具有两种抗原特异性的细胞；(iv) 未转导的细胞。在共转导的 CAR-T 细胞的制造过程中，由于 CAR 表达所需的细胞资源的竞争和/或其中一个细胞群的潜在优先扩增，存在着扭曲（skewed）转导和/或 CAR 群失衡的风险，而 CAR 群的不平衡可能会影响最佳双靶点的实现。与双顺反子盒（bicistronic cassette）相比，共转导通常可增强 CAR 表达，这是其优势之一。双顺反子 CAR-T 细胞在同一个 T 细胞中实现两个 CAR 双重表达的一个简单方法是使用包含双顺反子盒的单个载体。双顺反子载体包含两个基因，每个基因编码一个独特的 CAR，由一个「自裂解」肽分隔，能够平行共表达两个独立的 CAR，比例为 1:1。这种方法比联合给药或联合转导更简单、更便宜，因为每例患者只需要一个细胞产生和一个载体；且与共转导相比，双顺反子盒的产物更均一，因为所有转导的 T 细胞可在 T 细胞膜上表达两种 CAR。但这些载体需要更长的序列来编码两个完整的 CAR 分子，可能损害病毒包装（packaging），降低转导效率和破坏 CAR 表达。串联 CAR-T 细胞串联 CAR 由编码具有两个配体结合结构域的嵌合受体的单个载体产生，具有很多优点。与双顺反子 CAR 相比，结构尺寸明显更小，能够实现更好的包装。此外，它只需要一个载体，双 CAR-T 细胞产物更均一，并防止一个 CAR 相对于另一个 CAR 的优势。其缺点在于，串联 CAR 的最佳设计尚不明确，可能因使用的 scFv、靶向抗原的密度和靶向表位与 T 细胞膜的接近程度而异。很多参数都会影响 CAR 的效力，如 scFv 的顺序；每个 scFv 的 VH 和 VL 排列；VH 和 VL 之间或两个 scFv 之间的连接体长度；连接体的刚性。因此需要复杂的结构优化，包括多个 CAR 结构的生成和实证测试。在靶向 CD22 时串联 CAR 优化尤为重要，CD22 是一种低密度表达的抗原，高度糖基化，具有实质性的大小和刚性，可能损害免疫突触。总结尽管 CAR-T 细胞疗法的出现显著改善了 R/R ALL 和 NHL 患者的预后，但仍有相当比例的患者复发和死于疾病进展。这一现状促使了大量旨在靶向多抗原 (例如 CD19 和 CD20 或 CD22) 的新策略，旨在减轻抗原丢失或下调且不增加过度毒性。双靶点 CAR-T 可以通过多种手段实现，包括从简单的两种不同产品的联合给药到更复杂的双顺反子盒或串联 CAR 的设计。到目前为止，没有确凿的证据表明这些新型产品具有显著不同的毒性特征，但也没有证据表明其中一种策略优于其他策略，甚至没有证据表明双靶点优于单靶点，但抗原丢失已部分减少。部分双靶点 CAR-T 已与表观遗传学药物 (如地西他滨) 或检查点抑制剂 (如帕博利珠单抗和替雷利珠单抗) 联用，显示出有前景的疗效，且不增加毒性。其他组合包括常规 CD19 CAR-T 联合其他药物 (如抗 CD19 单克隆抗体 tafasitamab、双特异性单克隆抗体和抗体药物偶联物)。双靶点 CAR-T 的缺陷可能包括：(i) 未解决除抗原逃逸之外的其他耐药机制；(ii) 大多数临床试验随访不足；(3) 产品间异质性大，包括不同的额外靶点 (CD20、CD22 和其他)；(iv) 由于低传导效率和大尺寸的双顺反子和串联载体，导致需要复杂的制备优化。人们仍在寻找治疗 B 细胞恶性肿瘤的最佳产品和/或组合，但仍缺乏随机临床试验形式的明确证据 (但这正是人们热切期待的)。参考文献：Brillembourg H, Martínez-Cibrián N, Bachiller M, Alserawan L, Ortiz-Maldonado V, Guedan S, et al. The role of chimeric antigen receptor T cells targeting more than one antigen in the treatment of B-cell malignancies. Br J Haematol. 2024;00:1–11. https://doi.org/10.1111/ bjh.19348识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观不本站。