Affibody-based hBCMA x CD16 dual engagers for NK cell-mediated killing of multiple myeloma cells

Giang, Kim Anh; Boxaspen, Thorstein; Diao, Yumei; Nilvebrant, Johan; Kosugi-Kanaya, Mizuha; Kanaya, Minoru; Krokeide, Silje Zandstra; Lehmann, Fredrik; Svensson Gelius, Stefan; Malmberg, Karl-Johan; Nygren, Per-Åke

doi:10.1016/j.nbt.2023.09.002

Cited by 3 publications

(2 citation statements)

References 45 publications

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“…In addition, their safety profile makes these cells attractive targets for cancer immunotherapy. Many strategies are being currently explored to exploit NK cells for cancer treatment with promising preclinical efficacy achieved by chimeric antigen receptor (CAR)-NK cells and NK cell engagers bispecific antibodies in myeloma [19][20][21] . Yet, NK-cell-based therapies are limited due to the incomplete understanding of human NK cell heterogeneity and their potential changes within the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

“…NK cells also kill antibody-coated target cells through CD16 (FcgRIII), a process called antibody-dependent cellular cytotoxicity (ADCC), and these cells are critically involved in the anti-myeloma efficacy of anti-CD38 mAbs [15][16][17] . Finally, NK cells can acquire memory-like properties, such as long-term persistence and enhanced functions making these cells attractive therapeutic targets against myeloma 18 .Thus, accumulating evidence suggest the existence of an NK cell-mediated pressure in MM and there is a growing interest around their therapeutic manipulation [19][20][21] .…”

Section: Introductionmentioning

confidence: 99%

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Inflamed Natural Killer cells with adhesion defects are associated with a poor prognosis in Multiple Myeloma

Blanquart,

Ekren,

Rigaud

et al. 2024

Preprint

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The promising results obtained with immunotherapeutic approaches for multiple myeloma (MM) call for a better stratification of patients based on immune components. The most pressing being cytotoxic lymphocytes such as Natural Killer (NK) cells that are mandatory for MM surveillance and therapy. In this study, we performed a single cell RNA sequencing analysis of NK cells from 10 MM patients and 10 age/sex matched healthy donors (HD) that revealed important transcriptomic changes in NK cell landscape affecting both the bone marrow and peripheral blood compartment. The frequency of mature cytotoxic "CD56dim" NK cell subsets was reduced in MM patients at the advantage of late-stage NK cell subsets expressing NFkB and IFN-I inflammatory signatures. These NK cell subsets accumulating in MM patients were characterized by a low CD16 and CD226 expression and poor cytotoxic functions. MM CD16/CD226lo NK cells also had adhesion defects with reduced LFA-1 integrin activation and actin polymerization that may account for their limited effector functions in vitro. Finally, analysis of BM infiltrating NK cells in a retrospective cohort of 177 MM patients from the IFM 2009 trial demonstrated that a high frequency of NK cells and their low CD16 and CD226 expression were associated with a shorter overall survival. Thus, CD16/CD226lo NK cells with reduced effector functions accumulate along MM development and negatively impact patients' clinical outcome. Given the growing interest in harnessing NK cells to treat myeloma, this improved knowledge around MM-associated NK cell dysfunction will stimulate the development of more efficient immunotherapeutic drugs against MM.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inflamed Natural Killer cells with adhesion defects are associated with a poor prognosis in Multiple Myeloma

Blanquart,

Ekren,

Rigaud

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

Advances in adoptive cellular immunotherapy and therapeutic breakthroughs in multiple myeloma

Pu,

Liu,

Sharma

et al. 2024

Exp Hematol Oncol

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The basic idea of modulating the immune system to better recognize and fight tumor cells has led to the successful introduction of adoptive cellular immunotherapy (ACT). ACT-based treatment regimens, in which the patient's own immune cells are isolated and subsequently expanded (ex vivo) and reinfused, have also contributed significantly to the development of a personalized treatment strategy. Complementing this, the unprecedented advances in ACTs as chimeric antigen receptor (CAR)-T cell therapies and their derivatives such as CAR-NK, CAR-macrophages, CAR-γδT and CAR-NKT have further maximized the therapeutic outcomes. Herein, we provide a comprehensive overview of the development of ACTs in multiple myeloma (MM) and outline how they have evolved from an experimental form to a mainstay of standard clinical settings. Besides, we provide insights into cytokine-induced killer cell (CIK) therapy, an alternative form of ACT that (as CIK or CAR-CIK) has enormous potential in the clinical spectrum of MM. We also summarize the results of the major preclinical and clinical studies of adoptive cell therapy in MM and address the current challenges (such as cytokine release syndrome (CRS) and neurotoxicity) that limit its complete success in the cancer landscape.

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An anti-sortilin affibody-peptide fusion inhibits sortilin-mediated progranulin degradation

Ek,

Nilvebrant,

Nygren

et al. 2024

Front. Immunol.

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Heterozygous loss-of-function mutations in the GRN gene are a common cause of frontotemporal dementia. Such mutations lead to decreased plasma and cerebrospinal fluid levels of progranulin (PGRN), a neurotrophic factor with lysosomal functions. Sortilin is a negative regulator of extracellular PGRN levels and has shown promise as a therapeutic target for frontotemporal dementia, enabling increased extracellular PGRN levels through inhibition of sortilin-mediated PGRN degradation. Here we report the development of a high-affinity sortilin-binding affibody-peptide fusion construct capable of increasing extracellular PGRN levels in vitro. By genetic fusion of a sortilin-binding affibody generated through phage display and a peptide derived from the progranulin C-terminus, an affinity protein (A3-PGRNC15*) with 185-pM affinity for sortilin was obtained. Treating PGRN-secreting and sortilin-expressing human glioblastoma U-251 cells with the fusion protein increased extracellular PGRN levels up to 2.5-fold, with an EC50 value of 1.3 nM. Our results introduce A3-PGRNC15* as a promising new agent with therapeutic potential for the treatment of frontotemporal dementia. Furthermore, the work highlights means to increase binding affinity through synergistic contribution from two orthogonal polypeptide units.

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Affibody-based hBCMA x CD16 dual engagers for NK cell-mediated killing of multiple myeloma cells

Cited by 3 publications

References 45 publications

Inflamed Natural Killer cells with adhesion defects are associated with a poor prognosis in Multiple Myeloma

Inflamed Natural Killer cells with adhesion defects are associated with a poor prognosis in Multiple Myeloma

Advances in adoptive cellular immunotherapy and therapeutic breakthroughs in multiple myeloma

An anti-sortilin affibody-peptide fusion inhibits sortilin-mediated progranulin degradation

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