Development of BCMA-Targeted Bispecific Natural Killer Cell Engagers for Multiple Myeloma Treatment DOI Creative Commons

Minchuan Zhang,

Han Ping Loh,

Shiyi Goh Fang

et al.

Antibodies, Journal Year: 2024, Volume and Issue: 13(4), P. 97 - 97

Published: Nov. 29, 2024

Background: B-cell maturation antigen (BCMA)-targeted T cell-redirecting immunotherapies, including Chimeric Antigen Receptor (CAR) T-cell therapy and engagers have demonstrated remarkable success in treating relapsed/refractory (RR) multiple myeloma (MM), a malignancy of plasma cells. However, significant challenge is the severe side effects associated with overactivation, leading to cytokine release syndrome neurotoxicity MM patients undergoing such therapies. Bispecific NK cell (NKCEs) may offer promising alternative by redirecting cytotoxic activity towards tumor cells without triggering syndrome. Methods: In this study, we designed series BCMA × CD16 NKCEs that simultaneously engage on cells, respectively. We evaluated functionality these vitro respect their molecular design. Results: Our results indicate format design influences functionalities, underscoring importance selection optimizing NKCE-based therapies for MM. This study provides valuable insights developing next-generation advancing therapeutic strategies potentially other malignancies.

Language: Английский

Immune Cell Engagers: Advancing Precision Immunotherapy for Cancer Treatment DOI Creative Commons

H. In,

Minkyoung Park,

H.-K. Lee

et al.

Antibodies, Journal Year: 2025, Volume and Issue: 14(1), P. 16 - 16

Published: Feb. 11, 2025

Immune cell engagers (ICEs) are an emerging class of immunotherapies designed to harness the immune system's anti-tumor potential through precise targeting and activation effector cells. By engaging T cells, natural killer (NK) phagocytes, ICEs overcome challenges such as evasion MHC downregulation, addressing critical barriers in cancer treatment. T-cell (TCEs), led by bispecific (BiTEs), dominate field, with innovations half-life-extended BiTEs, trispecific antibodies, checkpoint inhibitory driving their application hematologic solid malignancies. NK (NKCEs) phagocyte (PCEs) rapidly progressing, drawing on cells' innate cytotoxicity macrophages' phagocytic abilities target tumors, particularly immunosuppressive microenvironments. Since FDA approval Blinatumomab 2014, have transformed oncology landscape, nine FDA-approved products numerous candidates clinical trials. Despite toxicity, resistance, limited efficacy ongoing research into advanced platforms combination therapies highlights growing provide personalized, scalable, effective treatments. This review investigates mechanisms, platforms, trends, progress ICEs, emphasizing pivotal role advancing precision immunotherapy promise a cornerstone next-generation therapies.

Language: Английский

Citations

1
Next-Generation Therapeutic Antibodies for Cancer Treatment: Advancements, Applications, and Challenges DOI
A. Raja,

Abhishek Kasana,

Vaishali Verma

et al.

Molecular Biotechnology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 2, 2024

Language: Английский

Citations

6
The antiviral potential of Vγ9Vδ2 T cells: Therapeutic implications for immunocompromised adult and pediatric hosts DOI

Veronica Bordoni,

Federica Guarracino,

Alessandro Lorusso

et al.

International review of cell and molecular biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
Structural basis of human cytomegalovirus neutralization by gB AD-5-specific potent antibodies DOI Creative Commons

Changwen Wu,

Nan Song, Yizhen Zhao

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(5), P. 115646 - 115646

Published: May 1, 2025

Human cytomegalovirus (hCMV) poses a severe threat to fetuses, newborns, and immunocompromised individuals. No approved vaccines limited treatment options are current medical challenges. Here, we analyze the human B cell responses glycoprotein (gB) in three top hCMV neutralizers from cohort of 283 individuals with latent-infected hCMV. By single-cell amplification memory cells, identify cluster potent neutralizing monoclonal antibodies (nAbs) that competitively recognize an unknown vulnerable site on gB antigenic domain 5 (AD-5). This nAbs functionally outperforms utilized clinical trials. Cryoelectron microscopy (cryo-EM) unveils structural basis neutralization mechanism antibody directly targeting fusion subdomain AD-5. Moreover, immunological analyses mouse sera have preliminarily validated potential superiority AD-5-focused immune responses. Overall, our results will support development optimized gB-based provide promising prophylactic therapeutic candidates against infection.

Language: Английский

Citations

0
Clinical development of tri-specific antibodies for immune-oncology DOI
Zhipeng Cao, Laura D. Osellame,

Laura Allan

et al.

Expert Opinion on Investigational Drugs, Journal Year: 2025, Volume and Issue: unknown

Published: May 23, 2025

Language: Английский

Citations

0
Cancer-Associated Fibroblast Proteins as Potential Targets against Colorectal Cancers DOI Open Access
Ruchi Shah, Katherine A. Johnson,

Anna E. L. Lippert

et al.

Cancers, Journal Year: 2024, Volume and Issue: 16(18), P. 3158 - 3158

Published: Sept. 14, 2024

In colorectal cancer (CRC), attempts to identify cell-specific markers guide antibody-mediated therapeutics have failed uncover that are both exclusive tissues and abundant across CRCs. Alternatively, cancer-associated fibroblasts (CAFs), which in the tumor microenvironment upregulate unique surface markers, not found healthy tissues. Here, we evaluated expression patterns of CAF-associated proteins α-smooth muscle actin (αSMA), fibroblast activation protein (FAP), podoplanin (PDPN), matrix metalloproteinase-2 (MMP2), transgelin (TAGLN), THY1. While αSMA THY1 were tissues, high abundance normal limited their targeting potential. FAP was present 94.5% primary metastatic CRC absent 93.7% adjacent colon liver assessed. These results indicate is a promising target for antibody conjugates with potential broad application CRC. Co-expression analyses showed CRCs simultaneously expressing levels PDPN, MMP2, enriched immune-related signatures, indicating immune engagers. Overall, this work highlights CAF act as therapeutic targets novel anticancer agents become important biomarkers.

Language: Английский

Citations

3
Mechanistic insights into resistance mechanisms to T cell engagers DOI Creative Commons
Liping Cao,

Gabrielle Leclercq-Cohen,

Christian Klein

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: April 22, 2025

T cell engagers (TCEs) represent a groundbreaking advancement in the treatment of B and plasma malignancies are emerging as promising therapeutic approach for solid tumors. These molecules harness cells to bind eliminate cancer cells, effectively bypassing need antigen-specific recognition. Despite their established clinical efficacy, subset patients is either refractory TCE (e.g. primary resistance) or develops resistance during course therapy acquired treatment-induced resistance). In this review we comprehensively describe mechanisms TCEs, occurring both preclinical models trials with particular emphasis on cellular molecular pathways underlying process. We classify these into tumor intrinsic extrinsic ones. Tumor encompass changes within that impact cell-mediated cytotoxicity, including antigen loss, expression immune checkpoint inhibitory ligands intracellular render resistant killing. involve factors external presence an immunosuppressive microenvironment (TME) reduced functionality. further propose actionable strategies overcome offering potential avenues enhancing efficacy clinic.

Language: Английский

Citations

0
Engaging T cells for cleanup DOI Creative Commons

Roman V Mungalov,

N.V. Mushenkova,

Dmitriy M. Chudakov

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: May 6, 2025

T-cell engagers represent a transformative approach to cancer immunotherapy leveraging bispecific and multispecific antibody constructs redirect cytotoxicity toward malignant cells. These molecules bridge T cells tumor by simultaneously binding CD3 on tumor-associated antigens cells, thereby enabling precise immune targeting even in immunologically “cold” tumors. Recent advancements include conditional activated microenvironment proteases minimize off-tumor toxicity as well receptor–based intracellular via MHC presentation. Clinical successes, such Kimmtrak metastatic uveal melanoma, underscore good potential of these modalities, while challenges persist the management cytokine release syndrome, neurotoxicity, resistance. Emerging are aimed at enhancing efficacy incorporation costimulatory signals, thus offering promising trajectory for next-generation immunotherapies. also gaining attention treatment autoimmune disorders, where they can be designed selectively modulate pathogenic responses. By autoreactive or B hold promise restoring tolerance conditions HLA-B*27–associated autoimmunity subtypes, multiple sclerosis, rheumatoid arthritis, type 1 diabetes mellitus. Engineering strategies that incorporate inhibitory receptors tissue-specific may further refine engagers’ therapeutic autoimmunity, minimizing systemic immunosuppression preserving homeostasis.

Language: Английский

Citations

0
Natural killer cells in neuroblastoma: immunological insights and therapeutic perspectives DOI Creative Commons
Magdalena Radoš,

Anna Landegger,

Lukas Schmutzler

et al.

Cancer and Metastasis Reviews, Journal Year: 2024, Volume and Issue: 43(4), P. 1401 - 1417

Published: Sept. 18, 2024

Language: Английский

Citations

2
Bispecific killer cell engagers employing species cross-reactive NKG2D binders redirect human and murine lymphocytes to ErbB2/HER2-positive malignancies DOI Creative Commons

Jordi Pfeifer Serrahima,

Katrin Schoenfeld,

Ines Kühnel

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Aug. 29, 2024

NKG2D is an activating receptor expressed by natural killer (NK) cells and other cytotoxic lymphocytes that plays a pivotal role in the elimination of neoplastic through recognition different stress-induced cell surface ligands (NKG2DL). To employ this mechanism for cancer immunotherapy, we generated NKG2D-engaging bispecific antibodies selectively redirect immune effector to expressing tumor-associated antigen ErbB2 (HER2). NKG2D-specific single chain fragment variable (scFv) cross-reactive toward human murine receptors were derived consecutive immunization chicken with antigens, followed stringent screening yeast display library. Four distinct species (sc) scFv domains selected, reformatted into engager format linking them via IgG4 Fc domain second specific ErbB2. The resulting molecules (termed scNKAB-ErbB2) as disulfide-linked homodimers, demonstrated efficient binding ErbB2-positive well NKG2D-expressing primary lymphocytes, NK-92 engineered chimeric from hNKAR mNKAR). Two scNKAB-ErbB2 found compete ligand MICA, while two engagers interacted epitope outside site. Nevertheless, all four tested similarly effective redirecting activity hNKAR-NK-92 mNKAR-NK-92 ErbB2-expressing targets, suggesting further development these immunotherapy warranted.

Language: Английский

Citations

1