Advancing T Cell Engagers in Multiple Myeloma: Structural Design and Clinical Optimization to Address Current Limitations.
- 1Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
- 2Key Laboratory of Biological Targeted Therapy (Huazhong University of Science and Technology), Ministry of Education, Wuhan, Hubei, People's Republic of China.
Abstract
T cell engagers (TCEs) have emerged as transformative agents in multiple myeloma, driving a paradigm shift through advances in molecular engineering and clinical application. This review examines these developments across structural design and clinical optimization. Structurally, the field has evolved from IgG-like formats enabling subcutaneous administration toward multi-specific architectures designed to circumvent antigen escape and enhance tumor selectivity. Clinically, strategies have been refined by early TCE integration to leverage preserved immune fitness, step-up dosing to mitigate cytokine release syndrome, and combinations with gamma-secretase inhibitors or immunomodulatory drugs to overcome resistance. However, key limitations persist: antigen loss and lineage plasticity; on-target/off-tumor depletion of normal plasma cells with hypogammaglobulinemia and infection; T-cell exhaustion under continuous exposure; and the absence of predictive biomarkers for response, toxicity, and sequencing. Future efforts should prioritize conditional or logic-gated formats that decouple potency from systemic exposure, target rotation to preempt escape, biomarker-driven selection with minimal residual disease-guided duration, and home-based subcutaneous delivery. Integrating bioengineering innovation with optimized clinical protocols while confronting these constraints will be essential for TCEs to deliver durable remissions and advance the prospect of a functional cure for MM.
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BibTeX
@article{cai2026advancing,
title = {{Advancing T Cell Engagers in Multiple Myeloma: Structural Design and Clinical Optimization to Address Current Limitations.}},
author = {Linyu Cai and Yuxuan Ding and Jinhua Wang and Lixin Quan and Qun Li and Guangqi Wang and Chi Ma and Chunyan Sun and Yu Hu},
journal = {Drug design, development and therapy},
year = {2026},
month = oct,
doi = {10.2147/dddt.s638795},
url = {https://europepmc.org/article/MED/42921550},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Advancing T Cell Engagers in Multiple Myeloma: Structural Design and Clinical Optimization to Address Current Limitations.
AU - Linyu Cai
AU - Yuxuan Ding
AU - Jinhua Wang
AU - Lixin Quan
AU - Qun Li
AU - Guangqi Wang
AU - Chi Ma
AU - Chunyan Sun
AU - Yu Hu
PY - 2026
DA - 2026/10/19
JO - Drug design, development and therapy
DO - 10.2147/dddt.s638795
UR - https://europepmc.org/article/MED/42921550
AB - T cell engagers (TCEs) have emerged as transformative agents in multiple myeloma, driving a paradigm shift through advances in molecular engineering and clinical application. This review examines these developments across structural design and clinical optimization. Structurally, the field has evolved from IgG-like formats enabling subcutaneous administration toward multi-specific architectures designed to circumvent antigen escape and enhance tumor selectivity. Clinically, strategies have been refined by early TCE integration to leverage preserved immune fitness, step-up dosing to mitigate cytokine release syndrome, and combinations with gamma-secretase inhibitors or immunomodulatory drugs to overcome resistance. However, key limitations persist: antigen loss and lineage plasticity; on-target/off-tumor depletion of normal plasma cells with hypogammaglobulinemia and infection; T-cell exhaustion under continuous exposure; and the absence of predictive biomarkers for response, toxicity, and sequencing. Future efforts should prioritize conditional or logic-gated formats that decouple potency from systemic exposure, target rotation to preempt escape, biomarker-driven selection with minimal residual disease-guided duration, and home-based subcutaneous delivery. Integrating bioengineering innovation with optimized clinical protocols while confronting these constraints will be essential for TCEs to deliver durable remissions and advance the prospect of a functional cure for MM.
SN - 1177-8881
ER -