Seminars in hematology最新文献

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.