Dapirolizumab pegol

In September, Biogen named HI-Bio’s former chief medical officer, Uptal Patel, M.D., as leader of its new western outpost.\n On its face, Biogen’s May 2024 acquisition of Human Immunology Biosciences (HI-Bio) looks just like many other deals in the biopharma world. A $1.15 billion upfront payment to secure a phase 3-ready monoclonal antibody is notable, but hardly unprecedented. Most observers would expect Biogen to bring the late-stage prize into its pipeline and scrap the rest of the biotech\'s assets. But Biogen didn\'t do that. Instead, it decided to use the HI-Bio buy for more, morphing the absorbed biotech into a West Coast Hub that has restored the company’s presence in California and brought the pharma closer to its scientific origins. And, in September, Biogen named HI-Bio’s former chief medical officer, Uptal Patel, M.D., as leader of its new western outpost.Patel’s mandate is to lead an expansion into immunology, primarily through a trifecta of phase 3 trials for felzartamab, the anti-CD38 antibody that Biogen bagged by buying HI-Bio. But while felzartamab’s late-stage development “takes up most of the energy and oxygen,” Patel told Fierce in an interview, his team is also looking to expand the asset into new indications alongside other, earlier-stage candidates that Biogen has brought in, like a preclinical C5aR1 antagonist from Vanqua Bio.“Biogen has probably acquired a reputation for being a neuroscience-focused company, but really its roots are in immunology,” Patel said. The launch of the West Coast Hub has “catalyzed a doubling down” on that history.  Looking back to move ahead Since taking the helm of Biogen in November 2022, Christopher Viehbacher has aimed to spread the pharma’s wings and expand into new therapeutic areas beyond the neuroscience field that had once proved a fertile source of new medicines.“While we remain committed to neuroscience, my personal view is that is not diversified enough for a company of our size,” the CEO said in an April 2024 earnings call. “The reality of neuroscience is that this is a high-risk area.” This risk was clearly demonstrated when Biogen shelved three neuro programs due to a “lower quality of success” just before Viehbacher took over.By launching an immunology-focused West Coast Hub, Biogen hopes to channel the science that first sparked the company’s Swiss founding in 1978.“Early on, cytokine signaling, all sorts of pathways that were relevant to immune-related diseases, became important,” Patel explained to Fierce. “Then they became targets in the neuro-immunology space, particularly with multiple sclerosis.”Two of Biogen’s founding scientists went on to win the Nobel Prize: Walter Gilbert, Ph.D., in 1980 for developing DNA sequencing and Phillip Allen Sharp, Ph.D., in 1993 for the discovery of gene regions called introns.Biogen ran some of the first studies of an antibody targeting CD40, a well-known immunology target, as did Idec Pharmaceuticals, which merged with Biogen in 2003. But the trials of both companies’ assets were halted by the FDA due to a risk of dangerous blood clots.“They learned from that, developed better assets, and have found really promising molecules that I think have a huge opportunity,” Patel said.One of these molecules, dapirolizumab pegol, has been jointly developed with UCB since 2003 and is currently being tested in a pair of phase 3 trials for systemic lupus erythematosus.It was the Idec merger that originally gave Biogen a home in California, but the company shuttered the San Diego campus in 2010.“Since then, the biotech ecosystem in the Bay Area and California sort of matured, but there hasn\'t been a real West Coast presence for Biogen,” Patel said. “It was really intentional to not just acquire us and have our team stay intact and continue to work on the West Coast, but to really develop a presence for Biogen here in South San Francisco,” the leader explained.HI-Bio’s Bay Area digs were modest, Patel added, with the hub since expanding to occupy an entire floor of Gateway of the Pacific’s Traverse center. There, Patel’s team works closely with Biogen’s bicoastal immunology research unit, led by San Francisco-based Nick Wilson, Ph.D., and can also benefit from the local talent pool.“This provided an opportunity to tap into the fantastic research and basic science infrastructure and talent on the West Coast,” Patel said.The hub has now grown to about 120 employees, a company spokesperson told Fierce, and Biogen plans to double the office space by the end of 2026 to make room for the still-expanding team.And while some turnover is always expected when one company buys another, Patel said, more than 90% of HI-Bio staff were retained in the first year after the acquisition.“What began as a 50-person site to cultivate HI-Bio’s culture and capabilities has grown into a 100-plus employee hub,” Jane Grogan, Ph.D., Biogen’s head of research, told Fierce in a statement. “Having an outpost in the region broadens our ability to attract top talent and take advantage of new opportunities both within and outside our walls to accelerate innovation for our pipeline.” Test trifecta Biogen’s leadership is convinced Patel is the right person to guide the pharma’s foray into immunology.“Dr. Patel brings a unique combination of clinical, development and research expertise that has deepened our understanding of immune-mediated diseases and advanced promising science into registrational studies,” CEO Viehbacher told Fierce in a statement. “His leadership in building the teams and global infrastructure necessary to launch three phase 3 trials this year reflects the speed and scale at which we aim [to] advance our immunology pipeline,” the CEO added.Those three phase 3 trials are for felzartamab, the star asset of Biogen’s HI-Bio acquisition. The pharma’s Pacific Coast outpost is now leading studies of the anti-CD38 antibody in the kidney conditions immunoglobulin A nephropathy, primary membranous nephropathy and antibody-mediated rejection of kidney transplants.CD38 is a well-established target for multiple myeloma, with Johnson and Johnson’s Darzalex (daratumumab) and Sanofi’s Sarclisa (isatuximab-irfc) fixtures on the market. German biopharma MorphoSys originally developed felzartamab to compete in the myeloma arena. Celgene struck a deal for the antibody in 2013, but walked away less than two years later without saying why, though investors speculated Celgene was unimpressed by the asset’s phase 1 data. HI-Bio came knocking in 2022, licensing the ex-China rights to felzartamab and global rights to an anti-C5aR1 antibody except for greater China and South Korea. The company settles on felzartamab as its anti-CD38 choice after surveying the broader field, Patel said, and finding that MorphoSys’ candidate had the most compelling safety profile.“It was developed specifically for immune-related diseases, not people with myeloma,” Patel explained. While other anti-CD38 antibodies tend to destroy blood cells when given to macaques, felzartamab doesn’t, so MorphoSys was able to collect long-term preclinical safety data on its molecule.“That chronic safety package is really important, because some of these patients with immune diseases are younger and potentially have childbearing potential,” Patel said. Though Patel is convinced that felzartamab has best-in-class potential, the hub team is also working to fashion longer-lasting, more effective versions of the antibody that can be delivered subcutaneously.When it comes to felzartamab and the rest of the immunology program, the West Coast Hub has a certain level of autonomy from broader Biogen influence, Patel said. But when it comes to expanding the pipeline, those choices are made with input from the entire company.“We have to work closely and be aligned as an organization, with commercial, with business development, with the research and development organizations broadly,” Patel said. “Because I report to Chris, [who is] part of the team that\'s evaluating all of the company\'s portfolio, we\'re able to have those discussions as they come up.”It’s obvious what attracted Biogen to HI-Bio last year: a promising late-stage asset, deep expertise in immunology and the chance to reestablish a presence on the West Coast. But HI-Bio, too, has highlighted advantages to being acquired by the historic pharma.“What drew us to this acquisition by Biogen as a partner is their commitment to foundational science that really gets at the underlying causes of disease,” Patel said. Now “it\'s just a matter of having the kind of growth that everybody”—including patients, shareholders and the company itself—“wins from.”

作者：周予西 陈小美 美工：何国红 罗真真 排版：马超 人体内的造血系统犹如一座精密的"生命工厂"，不断制造各类血细胞维持机体运转。而当这座工厂的"质量控制"系统出现故障，就会导致血液肿瘤的发生——源于造血细胞的恶性疾病，可以累及骨髓、血液及全身各个脏器和组织。 临床常见的血液肿瘤主要包括各种类型的白血病、多发性骨髓瘤、淋巴瘤、骨髓增生异常综合征、骨髓增殖性肿瘤等，其发病率和死亡率均居前列，是严重危害人类健康的重大疾病。血液瘤中发病人数最多的是白血病、多发性骨髓瘤和淋巴瘤。白血病约占血液瘤的36%，多发性骨髓瘤约占13%，淋巴瘤约占51%，三种血液瘤全球发病率超过13/10万人（图1）。 ▲ 图1 血液肿瘤概览 随着创新疗法的不断涌现，血液瘤药物市场持续扩容，其中大分子药物、CART等也成为治疗的重要方式。目前血液瘤大分子药物市场的“佼佼者”包括2024年全球销售额超百亿美元的CD38单抗，以及2025年业绩增长强劲的CART疗法和双抗药物，这些创新疗法是未来市场的重要增长点。 01 急性髓系白血病：精准分层的治疗新时代 急性髓系白血病（AML）是成年人中最常见的急性白血病，其特征是骨髓中未成熟髓系细胞的异常增殖和分化阻滞，导致正常造血功能衰竭。该疾病具有高度的遗传异质性，其发病机制涉及多种遗传学改变，包括染色体易位、基因突变和表观遗传学异常。这些分子异常共同导致细胞增殖、分化、凋亡等基本生命活动的失调，最终引发白血病的发生。 01 AML的临床治疗 对于能耐受强化疗的患者，以“7+3”方案（蒽环类药物+阿糖胞苷）为基石。针对FLT3突变阳性，则在此基础上联合Midostaurin已成为标准方案。对于不适合强化疗的患者，Venetoclax联合Azacitidine或Decitabine是广泛使用的新标准。在一线治疗无效或复发后，二线治疗的核心是靶向药物，例如针对FLT3突变可选用Gilteritinib，针对IDH2突变可使用Enasidenib。 在免疫治疗领域，目前已上市的药物相对较少。Gemtuzumab Ozogamicin是一款靶向CD33的抗体药物偶联物（ADC），已在海外获批用于治疗CD33阳性的AML，并且可通过临床急需药品临时进口通道在中国申请使用。 ▲ 图2 急性髓系白血病靶向治疗药物及其作用机制的示意图 02 AML在研靶点和新兴治疗 在AML靶点治疗领域，成熟靶点已展现扎实临床价值，新兴靶点与疗法则持续拓宽治疗边界。 ▷1）成熟靶点中，FLT3是核心之一，Gilteritinib已成为FLT3突变复发/难治AML的标准选择，新型FLT3/CHK1双靶点抑制剂TLX-83更瞄准耐药难题，为患者带来新希望； ▷2）CD33凭借ADC药物Gemtuzumab Ozogamicin在临床站稳脚跟； ▷3）针对NPM1突变或KMT2A重排的Menin抑制剂（如Ziftomenib）获FDA突破性疗法认定，在复发/难治患者中实现深度缓解，彰显精准治疗潜力。 从全球靶点研究热度看，CD33以103项研究位居榜首，FLT3也有26项研究布局，足见其在研发领域的核心地位，这些成熟靶点的持续深耕与创新药物迭代，为AML患者构建了坚实的治疗防线。 与此同时，新兴治疗手段正以多维度创新重塑AML治疗格局。 ▷1）细胞免疫领域，双靶点CAR-NK疗法通过同时靶向CD33和MSLN，结合基因编辑技术规避“自相残杀”，大幅提升疗效持久性，为细胞治疗开辟新路径； ▷2）双特异性抗体领域，针对CD33、CD123、FLT3及CLEC12A等靶点的T细胞衔接器正处于不同研究阶段，有望通过多靶点协同增强抗肿瘤活性。此外，从靶点研究分布可见，CD47、CD70等靶点也在快速推进，这些新兴方向不仅丰富了AML治疗的“武器库”，更有望突破现有治疗瓶颈，为患者带来更优的生存获益，凸显AML靶点治疗领域蓬勃的创新活力与广阔前景。 ▲ 图3 急性髓系白血病在研生物药物TOP20靶点进展情况（抗体类、偶联药物、细胞治疗） 02 多发性骨髓瘤：免疫治疗领跑下的突破 多发性骨髓瘤（MM）是仅次于非霍奇金淋巴瘤的第二大常见血液系统恶性肿瘤，其特征是骨髓中浆细胞的恶性增殖，并伴有单克隆免疫球蛋白（M蛋白）的过度产生。该疾病具有高度异质性，可根据M蛋白类型分为IgG型、IgA型、IgD型等多种亚型。 01 多发性骨髓瘤的临床治疗 在多发性骨髓瘤 (multiple myeloma, MM) 一线治疗中，适合自体干细胞移植 (ASCT) 的患者采用D-VRd方案；不适合移植的患者选用D-VMP方案或Isa-VRd方案 (Isatuximab+VRd) 。二线治疗针对CD38单抗耐药者，可选择BCMA靶向的CAR-T疗法 (如ide-cel、cilta-cel) 、ADC药物Belantamab mafodotin联合方案，或Pomalidomide为基础的方案 (如Lenalidomide耐药者可联用Elotuzumab、Dexamethasone) 。三线治疗聚焦“三重难治”患者，双特异性抗体 (如BCMA×CD3的Bictegravir、靶向GPRC5D的双抗) 、CAR-T疗法 (ide-cel、cilta-cel) 及核输出抑制剂Selinexor等创新疗法成为关键选择。 ▲ 图4 多发性骨髓瘤靶向治疗药物及其作用机制的示意图 02 MM在研靶点和新兴治疗 在多发性骨髓瘤（MM）靶点治疗领域，BCMA以296项研究位居全球靶点热度榜首，已成为成熟且极具潜力的核心靶点。 ▷1）其中，BCMA/CD3双特异性抗体Bictegravir已获批用于三线治疗，其ADC药物Blenrep也在欧盟获批联合方案； ▷2）CD38靶点有93项研究布局，Daratumumab和Elotuzumab为患者带来显著获益，尤其是为CD38单抗难治患者提供了新选择； ▷3）GPRC5D靶点研究热度紧随其后，其特异性双抗Talquetamab展现出超70%的客观缓解率，成为靶向治疗新亮点； ▷4）最新突破的FcRH5靶点，其双特异性抗体Cevostamab在I期临床中斩获88%的客观缓解率，因在几乎全部骨髓瘤细胞上表达，有望克服BCMA耐药，已计划直接进入III期临床试验。这些靶点的蓬勃研究与药物获批，为 MM 患者构建了从一线到后线的精准治疗矩阵。 与此同时，新兴治疗手段正通过多靶点创新与联合策略持续突破治疗瓶颈。 ▷1）例如，强生三特异性抗体JNJ-79635322可同时靶向BCMA、GPRC5D和CD3，I期临床推荐剂量组客观缓解率高达86%； ▷2）国内药企也在加速布局，武汉友芝友生物的双特异性抗体Y150（靶向CD38和CD3）已完成I期临床试验。这些多靶点抗体药物的研发，不仅丰富了MM治疗的“武器库”，更通过协同作用提升疗效、克服耐药，彰显出MM靶点治疗领域蓬勃的创新活力与广阔应用前景，为患者带来更多生存希望。 ▲ 图5 多发性骨髓瘤在研生物药物TOP20靶点进展情况（抗体类、偶联药物、细胞治疗） 03 淋巴瘤：异质性疾病的个体化治疗 淋巴瘤作为一组高度异质性的血液系统恶性肿瘤，其治疗策略高度依赖精准的病理分型和分子特征。当前国际权威诊疗指南（包括NCCN、ESMO和CSCO指南）均强调基于疾病亚型、分期及分子标志物的个体化治疗。 01 淋巴瘤的临床治疗 在淋巴瘤治疗中，一线治疗以R-CHOP免疫化疗方案为基石，针对存在MyD88 L265p或CD79B突变的弥漫大B细胞淋巴瘤患者，探索联合BTK抑制剂Zanubrutinib以提升疗效。二线治疗以靶向药物为核心，BTK抑制剂应用广泛，还探索“外泌体负载si-BTK与异欧前胡素 (ISOIM)” 的新型联合递送系统，针对原发性渗出性淋巴瘤等罕见类型，PI3K/mTOR双靶点抑制剂（如BGT226/Dactolisib）展现新潜力。三线治疗依赖创新机制药物，如新型PI3Kδ/HDAC6双靶点抑制剂（先导化合物22E）、高选择性PI3Kδ抑制剂（TYM-3-98）等。 ▲ 图6 淋巴瘤信号传导途径和靶向药物 02 淋巴瘤在研靶点和新兴治疗 在淋巴瘤靶点治疗领域：CD19、CD20、CD22等经典靶点的研发进入新阶段，其中CAR-T疗法雷尼基奥仑赛注射液(恒凯莱、HR001)在复发/难治性大B细胞瘤中显示持久缓解（3个月和6个月客观缓解率（ORR）分别是53.1%和45.7%），而CD20×CD3双特异性抗体通过T细胞介导的细胞毒作用开辟免疫治疗新路径，在中国市场，罗氏的Mosunetuzumab（商品名：皓罗华®）和Glofitamab均已获批用于治疗不同类型的淋巴瘤。 与此同时，新兴靶点与治疗手段正加速突破治疗瓶颈。 ▷1）CD30 CAR-T疗法（如武汉波睿达生物的BRD-01）在复发/难治性霍奇金淋巴瘤的临床试验中已显示出显著疗效与良好安全性。同时，针对CD40/CD40L通路的新药研发也在积极推进，其中激动剂抗体（如Mitazalimab）旨在激活免疫以治疗实体瘤，而拮抗剂抗体（如Frexalimab）则通过抑制该通路在自身免疫病（如多发性硬化）领域展现出潜力。此外，以EB病毒特异性抗原（如gp350）为靶点的CAR-T等新型细胞疗法，也为治疗EBV相关淋巴瘤提供了新的研究方向； ▷2）双特异性抗体与ADC药物的联合策略成效显著，III期研究证实CD20×CD3双抗Mosunetuzumab与CD79b ADC药物Polatuzumab Vedotin联用可使患者中位无进展生存期延长近3倍； ▷3）新一代“装甲CAR-T”通过分泌IL-18等细胞因子改善肿瘤微环境，显著提升治疗持久性。这些多维度的创新探索，不仅丰富了淋巴瘤治疗的“武器库”，更通过协同作用与机制革新，为患者带来更多生存希望，彰显出淋巴瘤靶点治疗领域蓬勃的创新活力与广阔应用前景。 ▲ 图7 淋巴瘤在研生物药物TOP20靶点进展情况（抗体类、偶联药物、细胞治疗） 04 总结 血液肿瘤治疗将在靶点创新与技术迭代中持续进阶。FLT3/CHK1双靶点抑制剂、FcRH5等新靶点研究将破解耐药困局；多特异性抗体、“装甲CAR-T”等创新疗法通过多机制协同，进一步提升疗效与安全性。随着精准靶向与免疫治疗的深度融合，血液肿瘤治疗的治愈边界将不断拓展，为抗体生物领域创新发展注入强劲动能。 Sanyou 10th Anniversary | Revolutionizing Hematologic Oncology Treatment — Ushering in the Era of Precision Stratified Therapy The hematopoietic system in the human body operates like a precise "life factory," continuously producing various blood cells to maintain bodily functions. When the "quality control" system of this factory malfunctions, hematologic malignancies can arise—malignant diseases originating from hematopoietic cells that can affect the bone marrow, blood, and various organs and tissues throughout the body. Clinically common hematologic malignancies primarily include various types of leukemia, multiple myeloma, lymphoma, myelodysplastic syndromes, and myeloproliferative neoplasms. Their incidence and mortality rates rank high, making them significant diseases that seriously endanger human health. Among hematologic tumors, the most prevalent in terms of case numbers are leukemia, multiple myeloma, and lymphoma. Leukemia accounts for approximately 36% of hematologic tumors, multiple myeloma for about 13%, and lymphoma for about 51%. The global combined incidence rate of these three hematologic tumors exceeds 13 per 100,000 people (Figure 1). ▲ Figure 1. Overview of Hematologic Malignancies   With the continuous emergence of innovative therapies, the drug market for hematologic tumors continues to expand. Among these, macromolecular drugs and CAR-T have become important treatment modalities. Current "standout" products in the hematologic tumor macromolecular drug market include CD38 monoclonal antibodies with global sales exceeding $10 billion in 2024, as well as CAR-T therapies and bispecific antibodies showing strong performance growth in 2025. These innovative therapies represent key future growth drivers for the market. 01 Acute Myeloid Leukemia: A New Era of Precision Stratified Treatment Acute Myeloid Leukemia (AML) is the most common acute leukemia in adults, characterized by the abnormal proliferation and blocked differentiation of immature myeloid cells in the bone marrow, leading to failure of normal hematopoiesis. This disease exhibits high genetic heterogeneity, and its pathogenesis involves various genetic alterations, including chromosomal translocations, gene mutations, and epigenetic abnormalities. These molecular aberrations collectively disrupt fundamental cellular processes like proliferation, differentiation, and apoptosis, ultimately leading to the development of leukemia. 01 Clinical Management of AML For patients eligible for intensive chemotherapy, the "7+3" regimen (anthracycline + cytarabine) serves as the cornerstone. For those with FLT3 mutations, the addition of Midostaurin to this backbone has become the standard of care. For patients unsuitable for intensive chemotherapy, the combination of Venetoclax with Azacitidine or Decitabine is a widely used new standard. After first-line treatment failure or upon relapse, targeted agents form the core of second-line therapy. For instance, Gilteritinib can be chosen for FLT3 mutations, and Enasidenib can be used for IDH2 mutations. In the realm of immunotherapy, currently approved drugs are relatively few. Gemtuzumab Ozogamicin is an antibody-drug conjugate (ADC) targeting CD33, approved overseas for treating CD33-positive AML and accessible in China through the clinical urgent drug importation pathway. ▲ Figure 2. Schematic diagram of targeted therapeutic drugs and their mechanisms of action in Acute Myeloid Leukemia   02 Investigational Targets and Emerging Therapies in AML   In the field of AML targeted therapy, established targets have demonstrated solid clinical value, while emerging targets and therapies continue to expand the treatment landscape. Among the mature targets:  ▷1) FLT3 is a core one, with Gilteritinib established as a standard option for relapsed/refractory FLT3-mutated AML. The novel FLT3/CHK1 dual-target inhibitor TLX-83 specifically addresses the challenge of resistance, offering new hope for patients.  ▷2) CD33 has secured its place in the clinic with the ADC drug Gemtuzumab ozogamicin.  ▷3) Menin inhibitors (e.g., Ziftomenib) targeting NPM1 mutations or KMT2A rearrangements have received FDA Breakthrough Therapy designation, achieving deep responses in relapsed/refractory patients and highlighting the potential of precision medicine. From a global perspective of target research popularity, CD33 leads with 103 active studies, and FLT3 also has 26 research programs, underscoring their central role in the R&D landscape. The continued in-depth research and iterative innovation of drugs against these established targets are building a solid line of defense for AML patients. Concurrently, emerging therapeutic approaches are reshaping the AML treatment paradigm through multi-dimensional innovation.  ▷1) In the cellular immunotherapy domain, dual-target CAR-NK therapies targeting both CD33 and MSLN, combined with gene-editing technology to avoid "fratricide," significantly enhance the durability of efficacy, opening new pathways for cell therapy.  ▷2) In the bispecific antibody field, T-cell engagers targeting antigens like CD33, CD123, FLT3, and CLEC12A are in various stages of investigation, promising enhanced anti-tumor activity through multi-target synergy. Furthermore, the distribution of target research indicates that other targets like CD47 and CD70 are also advancing rapidly. These emerging directions not only enrich the AML treatment "arsenal" but also hold the potential to break through current therapeutic bottlenecks, offering patients improved survival benefits. This highlights the vibrant innovative activity and broad prospects within the AML targeted therapy field. ▲ Figure 3. Progress of TOP 20 Investigational Biological Drug Targets in Acute Myeloid Leukemia (Antibody-based, Conjugated Drugs, Cell Therapy)   02 Multiple Myeloma: Breakthroughs Led by Immunotherapy Multiple Myeloma (MM) is the second most common hematologic malignancy after non-Hodgkin lymphoma, characterized by the malignant proliferation of plasma cells in the bone marrow, accompanied by the overproduction of a monoclonal immunoglobulin (M protein). The disease is highly heterogeneous and can be classified into various subtypes such as IgG, IgA, and IgD types based on the M protein isotype. 01 Clinical Management of Multiple Myeloma In the first-line treatment of Multiple Myeloma (MM), patients eligible for autologous stem cell transplantation (ASCT) receive the D-VRd regimen (Daratumumab + Bortezomib + Lenalidomide + Dexamethasone). For transplant-ineligible patients, the D-VMP regimen (Daratumumab + Bortezomib + Melphalan + Prednisone) or the Isa-VRd regimen (Isatuximab + VRd) are chosen. Second-line therapy for patients refractory to CD38 monoclonal antibodies may include BCMA-targeted CAR-T therapies (e.g., Ide-cel, Cilta-cel), the ADC drug Belantamab mafodotin in combination regimens, or Pomalidomide-based regimens (e.g., combined with Elotuzumab and Dexamethasone for those refractory to Lenalidomide). Third-line therapy focuses on "triple-class refractory" patients, where innovative therapies such as bispecific antibodies (e.g., the BCMAxCD3 bispecific Bictegravir, bispecifics targeting GPRC5D), CAR-T therapies (Ide-cel, Cilta-cel), and the nuclear export inhibitor Selinexor become crucial options. ▲ Figure 4. Schematic diagram of targeted therapeutic drugs and their mechanisms of action in Multiple Myeloma 02 Investigational Targets and Emerging Therapies in MM In the field of Multiple Myeloma (MM) targeted therapy, BCMA ranks first globally in research popularity with 296 studies, establishing itself as a mature and highly promising core target.  ▷1) Among these, the BCMA/CD3 bispecific antibody Bictegravir has been approved for third-line use, and its ADC counterpart Blenrep is also approved in the EU in combination regimens.  ▷2) The CD38 target has 93 active studies; Daratumumab and Elotuzumab have provided significant patient benefit, particularly offering new options for patients refractory to CD38 monoclonal antibodies. ▷3) Research on the GPRC5D target follows closely in popularity, with its specific bispecific antibody Talquetamab demonstrating an objective response rate exceeding 70%, emerging as a new highlight in targeted therapy.  ▷4) The recently targeted FcRH5 antigen, with its bispecific antibody Cevostamab achieving an 88% objective response rate in Phase I trials, shows potential to overcome BCMA resistance due to its expression on nearly all myeloma cells. Plans are underway to proceed directly to Phase III clinical trials. The vigorous research and drug approvals surrounding these targets are constructing a precision treatment matrix for MM patients from first to later lines of therapy. Simultaneously, emerging therapeutic strategies are continuously pushing the boundaries of treatment through multi-target innovation and combination approaches.  ▷1) For example, Johnson & Johnson's trispecific antibody JNJ-79635322, targeting BCMA, GPRC5D, and CD3 simultaneously, achieved a high 86% objective response rate at the recommended Phase II dose in Phase I studies.  ▷2) Domestic pharmaceutical companies are also accelerating their pipelines; for instance, Wuhan YZY Biopharma's bispecific antibody Y150 (targeting CD38 and CD3) has completed Phase I clinical trials. The development of these multi-target antibody drugs not only enriches the MM treatment "arsenal" but also enhances efficacy and overcomes resistance through synergistic effects, demonstrating the dynamic innovation and broad application prospects in the MM targeted therapy landscape, bringing more hope for survival to patients. ▲ Figure 5. Progress of TOP 20 Investigational Biological Drug Targets in Multiple Myeloma (Antibody-based, Conjugated Drugs, Cell Therapy) 03 Lymphoma: Personalized Therapy for a Heterogeneous Disease Lymphoma represents a group of highly heterogeneous hematologic malignancies whose treatment strategies heavily rely on precise pathological classification and molecular profiling. Current authoritative international treatment guidelines (including NCCN, ESMO, and CSCO) all emphasize individualized treatment based on disease subtype, stage, and molecular markers.   01 Clinical Management of Lymphoma In lymphoma treatment, first-line therapy is cornerstoneed by the R-CHOP immunochemotherapy regimen. For patients with diffuse large B-cell lymphoma harboring MyD88 L265p or CD79B mutations, exploration of combining the BTK inhibitor Zanubrutinib is underway to improve efficacy. Second-line therapy centers on targeted agents. BTK inhibitors are widely used, and novel approaches like a "novel delivery system loading si-BTK and Isoimperatorin (ISOIM)" are being explored. For rare types like primary effusion lymphoma, PI3K/mTOR dual-target inhibitors (e.g., BGT226/Dactolisib) show new potential. Third-line treatment relies on drugs with innovative mechanisms, such as novel PI3Kδ/HDAC6 dual-target inhibitors (lead compound 22E) and highly selective PI3Kδ inhibitors (TYM-3-98). ▲ Figure 6. Lymphoma Signal Transduction Pathways and Targeted Drugs   02 Investigational Targets and Emerging Therapies in Lymphoma In the field of lymphoma targeted therapy, research on classic targets like CD19, CD20, and CD22 has entered a new stage. The CAR-T therapy Reni Orelen Syringe Solution (恒凯莱®, HR001) has demonstrated durable responses in relapsed/refractory large B-cell lymphoma (with 3-month and 6-month objective response rates (ORR) of 53.1% and 45.7%, respectively). Meanwhile, CD20×CD3 bispecific antibodies are pioneering new paths in immunotherapy by mediating T cell-dependent cytotoxicity. In the Chinese market, Roche's Mosunetuzumab (trade name: 皓罗华®) and Glofitamab have been approved for treating different types of lymphoma. Concurrently, emerging targets and therapeutic modalities are rapidly advancing to overcome treatment bottlenecks.  ▷1) CD30 CAR-T therapy (e.g., Wuhan Borui Biotechnology's BRD-01) has shown significant efficacy and a favorable safety profile in clinical trials for relapsed/refractory Hodgkin Lymphoma. Development of drugs targeting the CD40/CD40L pathway is also progressing actively. Agonist antibodies (e.g., Mitazalimab) aim to activate the immune system against solid tumors, while antagonist antibodies (e.g., Frexalimab) show potential in autoimmune diseases like multiple sclerosis by inhibiting this pathway. Furthermore, novel cell therapies targeting Epstein-Barr virus (EBV) specific antigens (e.g., gp350) provide new research directions for treating EBV-associated lymphomas.  ▷2) Combination strategies employing bispecific antibodies and ADCs have shown marked success. A Phase III study confirmed that combining the CD20×CD3 bispecific antibody Mosunetuzumab with the CD79b ADC drug Polatuzumab Vedotin nearly tripled the median progression-free survival of patients.  ▷3) Next-generation "Armored CAR-T" cells, designed to secrete cytokines like IL-18 to modify the tumor microenvironment, significantly enhance the durability of responses. These multi-dimensional innovative explorations not only enrich the lymphoma treatment "arsenal" but also, through synergistic effects and mechanistic innovations, offer patients greater hope for survival, highlighting the vigorous innovative activity and broad application prospects in the lymphoma targeted therapy field. ▲ Figure 7. Progress of TOP 20 Investigational Biological Drug Targets in Lymphoma (Antibody-based, Conjugated Drugs, Cell Therapy) 04 Summary The treatment of hematologic malignancies will continue to advance through target innovation and technological iteration. Novel targets like FLT3/CHK1 dual inhibitors and FcRH5 aim to 破解 overcome resistance challenges. Innovative therapies such as multispecific antibodies and "Armored CAR-T" further enhance efficacy and safety through multi-mechanistic synergy. With the deepening integration of precision targeting and immunotherapy, the boundaries of curability for hematologic tumors are continually expanding, injecting powerful momentum into the innovative development of the antibody and biologics field. ▶ References: (Sant M, Allemani C, Tereanu C, et al. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project[J]. Blood, The Journal of the American Society of Hematology, 2010, 116(19): 37243734.) (YE Xiangjun, LU Xingguo. Interpretation of the 5th edition of the WHO classification of haematolymphoid tumours on MDS and AML[J]. Journal of Diagnostics Concepts & Practice, 2023, 22(05): 421428.) (5th edition of the WHO Classification of Haematolymphoid Tumours.) (Zhonghua Xue Ye Xue Za Zhi [Chinese Journal of Hematology], 2023,44(9) : 705712.) (Haubner S, Subklewe M, Sadelain M. Honing CAR T cells to tackle acute myeloid leukemia[J]. Blood, 2025, 145(11): 11131125) (Song F, Lin S, Xu T, et al. Targeted therapy in acute myeloid leukemia: resistance and overcoming strategy[J]. Drug Resistance Updates, 2025: 101286) (Lentzsch S, Ehrlich L, Roodman G. Pathophysiology of multiple myeloma bone disease. Hematol Oncol Clin North Am. 2007;21(6):10351049, viii. DOI: 1016/j.hoc.2007.08.009.) (Pinto V et al. Multiple Myeloma: Available Therapies and Causes of Drug Resistance. Cancers. 2020; 12(2):407.) (Chinese Medical Doctor Association Hematology Branch, Chinese Society of Hematology. Chinese Guidelines for the Diagnosis and Management of Multiple Myeloma (2024 Revision) [J]. Zhonghua Nei Ke Za Zhi, 2024, 63(12): 11861195. DOI: 10.3760/cma.j.cn1121382024092800616.) (Nishida, H. Rapid Progress in Immunotherapies for Multiple Myeloma: An Updated Comprehensive Review. Cancers 2021, 13, 2712.) (Lewis W D, Lilly S, Jones K L. Lymphoma: diagnosis and treatment[J]. American family physician, 2020, 101(1): 3441.) (Shankland K R, Armitage J O, Hancock B W. Nonhodgkin lymphoma[J]. The Lancet, 2012, 380(9844): 848857.) (Wang L, Qin W, Huo Y J, et al. Advances in targeted therapy for malignant lymphoma[J]. Signal transduction and targeted therapy, 2020, 5(1): 15.) (Yung L, Linch D. Hodgkin's lymphoma[J]. The lancet, 2003, 361(9361): 943951.) (Connors J M, Cozen W, Steidl C, et al. Hodgkin lymphoma[J]. Nature Reviews Disease Primers, 2020, 6(1): 61.) (Hennessy B T, Hanrahan E O, Daly P A. NonHodgkin lymphoma: an update[J]. The lancet oncology, 2004, 5(6): 341353.) 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