Seminars in hematology最新文献

T-cell engaging bispecific antibodies (BsAbs) have transformed the treatment paradigms for B-cell non-Hodgkin lymphomas. This review focused on 4 CD20 × CD3 BsAbs, as well as surovatamig, a CD19 × CD3 BsAb currently under investigation that has demonstrated promising efficacy against relapsed/refractory B-cell lymphomas. All 4 CD20 × CD3 BsAbs are approved as third-line and beyond therapies: mosunetuzumab for follicular lymphoma (FL), glofitamab for diffuse large B-cell lymphoma (DLBCL), and epcoritamab and odronextamab for both FL and DLBCL (the latter in European Union only). Although all are T-cell-directed immunotherapies, they differ in their development platforms, structural configurations, and routes of administration. The safety profile is characterized by T-cell overactivation-related events, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). CRS was observed in nearly half of patients and mostly low grade with different mitigation strategies across BsAbs. The incidence of ICANS was mostly below 10%, with grade ≥ 3 events being rare. Multiple studies are currently evaluating these agents in both the relapsed/refractory and frontline settings, either as monotherapy or in combination with other agents. This review summarizes the efficacy and safety of each agent across B-cell lymphoma subtypes, along with their dosing schedules and CRS mitigation strategies.

Neutrophils, the most abundant innate immune cell population in human circulation, serve as frontline defenders through canonical mechanisms including degranulation, generation of reactive oxygen species (ROS), and neutrophil extracellular trap (NET) formation. Beyond their classical antimicrobial functions, emerging evidence positions neutrophils as critical effectors in antibody-based cancer immunotherapy. Through Fc receptor-mediated mechanisms, such as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and trogocytosis, as well as strategies engaging the IgA-FcαRI (CD89) axis, neutrophils elicit enhanced antitumor responses compared to conventional IgG-based modalities. Building upon this framework, therapeutic approaches have progressed from granulocyte colony-stimulating factor (G-CSF)-mediated neutrophil expansion to bispecific antibody platforms that actively redirect neutrophils toward tumor cells, with proof-of-concept established in hematologic malignancies through CD89-targeting bispecific formats. However, in solid tumors, the immunosuppressive tumor microenvironment (TME) and skewing toward a protumorigenic N2 phenotype substantially hinder neutrophil-mediated cytotoxicity. To overcome these limitations, recent efforts have focused on reprogramming neutrophil functions through TGF-β blockade and rational immunotherapeutic combinations. Collectively, these integrative strategies offer the potential to reposition neutrophils from classical innate immune sentinels to dynamic effectors in antibody-based cancer immunotherapy.

B-cell maturation antigen (BCMA; TNFRSF17) has rapidly evolved from a plasma cell survival receptor within the BAFF/APRIL network to a central therapeutic hub in multiple myeloma (MM). In this review, we first outline the gene organization, expression pattern, and ligand biology of BCMA in the context of its sister receptors BAFF-R and TACI, emphasizing shared structural motifs-such as the conserved helix-loop-helix hairpin and DxL motif-that govern APRIL/BAFF recognition. We next detail how BCMA-proximal signaling through TRAF adaptors integrates canonical and noncanonical NF-κB, MAPK, and PI3K-AKT pathways to sustain long-lived plasma cells and drive myeloma progression, and how γ-secretase-mediated shedding generates soluble BCMA (sBCMA), which function as both a dynamic disease biomarker and an antigen sink for BCMA-directed agents. We then summarize the clinical development and distinguishing features of currently approved BCMA-targeted modalities-CAR T-cell therapies (ide-cel, cilta-cel), bispecific T-cell engagers (teclistamab, elranatamab, linvoseltamab), and the antibody-drug conjugate (belantamab mafodotin)-highlighting their efficacy, toxicity profiles, and practical positioning in relapsed/refractory MM. Finally, we review emerging resistance mechanisms, including γ-secretase-driven sBCMA elevation, ligand-rich APRIL/BAFF niches, and therapy-induced TNFRSF17 lesions, ranging from biallelic deletions to epitope-altering missense mutations and in-frame deletions within the BCMA extracellular domain. These insights inform rational strategies such as γ-secretase inhibition, dual-target CAR T-cells and bispecific T-cell engagers.

Glioblastoma (GBM) remains one of the most lethal primary brain tumors, with current standard therapies conferring only limited survival benefit. Although immunotherapeutic approaches have expanded treatment options, they have yet to demonstrate consistent and durable efficacy. Chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising platform with the potential to overcome critical limitations of existing strategies. This review highlights the unique advantages of CAR-T therapy in complementing both standard and immune-based treatments. It further summarizes clinical outcomes reported to date, encompassing completed and ongoing trials, and underscores recurring barriers such as antigen heterogeneity, limited persistence, and the profoundly immunosuppressive tumor microenvironment. In view of these challenges, we discuss emerging strategies to advance CAR-T therapy in GBM, including approaches to broaden antigen recognition, enhance effector function, improve safety, and explore alternative cellular platforms. With continued innovation and rigorous clinical evaluation, CAR-T therapy holds considerable promise for delivering meaningful and durable benefit to patients with GBM.

First-generation T-cell engagers have demonstrated significant efficacy in treating hematological malignancies by providing a potent T-cell receptor Signal 1. However, their efficacy is limited by the absence of a TCR co-stimulatory Signal 2, which results in T-cell exhaustion and resistance. A new strategy that addresses this issue is the use of bispecific antibodies (bsAbs) that target co-stimulatory Signal 2. These bispecific antibodies (bsAbs) co-engage a cancer-associated antigen (CAA) with a T-cell co-stimulatory receptor, such as CD28 or 4-1BB. Recent clinical strategies have combined Signal 1 and Signal 2 engagers in dual-bispecific regimens for lymphoma and multiple myeloma treatment. Therefore, the "Signal 1 + Signal 2" approach represents a significant advancement in immunotherapy, offering the potential to achieve deeper responses, overcome drug resistance and establish a robust 'off-the-shelf' therapeutic platform.

Antibody-drug conjugates (ADCs) have transformed the treatment of hematologic malignancies by coupling antibody selectivity with potent cytotoxic payloads. Their clinical performance depends largely on chemical design, particularly linker stability and conjugation strategy. Advances in site-specific and site-selective platforms, such as ThioMab, GlycoConnect, AJICAP, and AbClick, enable homogeneous ADCs with controlled drug-to-antibody ratio (DAR) and improved safety. Cleavable linkers-protease-sensitive, acid-labile, and redox-responsive-facilitate intracellular drug release, while non-cleavable and solubility-enhancing designs improve stability and pharmacokinetics (PK). Case studies of FDA-approved ADCs, including brentuximab vedotin, polatuzumab vedotin, inotuzumab ozogamicin, and loncastuximab tesirine, demonstrate how these innovations translate into therapeutic benefit. Nonetheless, challenges such as antigen heterogeneity, resistance mechanisms, and off-target toxicities persist. By integrating advances in conjugation chemistry, linker engineering, and payload selection, next-generation ADCs are poised to expand efficacy and safety in hematologic oncology and further refine targeted therapy in blood cancers.

Significant advances have been made in the treatment of multiple myeloma, with B-cell maturation antigen (BCMA)-targeting immunotherapies at the forefront of these developments. Three treatment modalities-including antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor-T cell therapies-have demonstrated durable responses, each associated with class-specific unique adverse events. Moreover, their efficacy and safety in later stages of multiple myeloma also provide the rationale for their use in earlier lines of therapy. In this review, we briefly outline the background biology of BCMA and discuss the mechanisms of action and structural features of these 3 agents, together with the most recent clinical data from early-phase trials. We also describe class-specific adverse events and mechanisms of resistance, as well as strategies to overcome them, thereby offering a framework to catch up with future developments in BCMA-targeted immunotherapy for multiple myeloma.

The success of bispecific T cell engagers (BiTEs) in hematological malignancies has catalyzed the development of trispecific antibodies that simultaneously target 3 molecular entities. These next-generation immunotherapeutics address the key limitations of bispecific constructs including antigen escape, limited T cell activation, and on-target off-tumor toxicity. Trispecific constructs employ 2 primary strategies: dual tumor antigen targeting combined with CD3 engagement to prevent antigen escape, and integration of co-stimulatory signals (CD28, 4-1BB) to enhance T cell function. Early clinical data demonstrated promising efficacy signals, particularly in multiple myeloma where BCMA×CD38×CD3 constructs achieved 90% overall response rates in early-phase trials. Safety profiles mirror bispecific antibodies with cytokine release syndrome and neurotoxicity as primary concerns. Trispecific T cell engagers represent a significant advancement in precision immunotherapy for hematological malignancies. Although early clinical results are encouraging, challenges remain in optimal target selection, manufacturing complexity, and resistance mechanisms. Ongoing clinical trials will define their role in the evolving treatment landscape.

Emerging antibody-based therapeutic modalities such as CAR-Ts and bispecific antibodies have proven highly efficacious in treating diseases, including hematological malignancies. However, the complex molecular architectures of these novel agents present significant challenges in their design and production, for which binding moieties with small size and favorable physicochemical properties may offer a promising solution. Single domain antibodies (sdAbs), typically derived from the heavy chain antibodies of camelids and cartilaginous fishes but increasingly from synthetic and other sources as well, are small (12-15 kDa), well expressed, and exhibit favorable physicochemical properties, making them ideal targeting domains for these new modalities. In this article, we review the origins and characteristics of sdAbs, along with recent studies on CAR-T cell therapies and bispecific antibodies for hematological malignancies that incorporate sdAbs into their constructs, with emphasis on their structures, binding properties, and therapeutic efficacies. Together, these developments underscore the promise of sdAb-based CAR-Ts and bispecific antibodies as next-generation therapeutics, with the potential to expand treatment options and improve outcomes in hematological malignancies and beyond.

Bispecific T cell engagers (bispecific TCEs) are engineered antibodies that redirect T cells to mediate tumor cell killing by simultaneously binding to CD3 on T cells and tumor-associated antigens. As of July 2025, ten bispecific TCEs are clinically available. The CD3-binding antibodies in these bispecific TCEs can be classified into 6 groups based on the amino acid sequence similarity across their 6 complementarity-determining regions (CDRs). Specifically, antibodies were assigned to the same family if their six CDRs-HCDR1-3 and LCDR1-3-exhibited ≥80% pairwise sequence identity upon multiple sequence alignment. Family 1, derived from OKT3-a mouse hybridoma generated by immunizing BALB/c mice with human T cells-includes only blinatumomab; Family 2, derived from SP34-a rhesus monkey (Macaca mulatta) derived hybridoma specific for human T cells-comprises 5 antibodies; and Family 6, derived from UCHT1-a mouse hybridoma generated by immunizing mice with human T cells-contains only tebentafusp. The origin of the remaining 3 antibodies has not been disclosed and they possess unique CD3-binding sequences. We classified them into their own distinct families (Families 3, 4, and 5). Interestingly, mosunetuzumab (Family 4) showed remarkably lower incidence of adverse events such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and infection compared to other bispecific TCEs even though its affinity for CD3ε was not significantly different. The epitopes of 4 antibodies in Family 2, teclistamab, talquetamab, glofitamab, and tarlatamab were previously defined to be located at the N-terminal region of CD3ε via hydrogen-deuterium exchange mass spectrometry (HDX-MS) analysis. In our in silico epitope prediction analysis, the N-terminal region was included in the epitope region of all bispecific TCEs regardless of their family. Blinatumomab (Family 1) and tebentafusp (Family 6) did not bind to the CD3ε homolog of the cynomolgus monkey, whereas the other 8 bispecific TCEs did. This lack of cross-reactivity poses clear disadvantages in their preclinical development, particularly for toxicity and safety evaluation in nonhuman primate models.