Development of a variant of dinutuximab with enhanced antitumor efficacy and reduced induction of neuropathic pain

Liu, Xin‐Yuan; Chen, Yi‐Li; Liu, Guo‐Jian; Deng, Xiang-nan; Cui, Yue; Tan, Jie; Dong, Xingchen; Li, Hua‐Ying; Chen, Gan‐Jun; Ou, Zhimin; Wang, Chunhe

doi:10.1002/2211-5463.13464

Cited by 3 publications

(1 citation statement)

References 42 publications

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“…The valency of the interaction is an important criterion for the high binding affinity of an antibody or antibody fragment when interacting with ganglioside GD2, a carbohydrate antigen [ 31 ]. In this regard, approaches that enhance the cytotoxic activity of FDCs by increasing the valency of binding to GD2, for example, by multimerization of the antigen-binding moieties [ 29 ], or by increasing the affinity of binding to GD2 by affinity maturation [ 32 ], are of particular interest. The FDCs obtained in this work are inferior in efficacy to the anti-GD2 full-length antibody-drug conjugates studied by us before [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

Minibody-Based and scFv-Based Antibody Fragment-Drug Conjugates Selectively Eliminate GD2-Positive Tumor Cells

Kalinovsky

Холоденко

Kibardin

et al. 2023

IJMS

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Ganglioside GD2 is a well-established target expressed on multiple solid tumors, many of which are characterized by low treatment efficiency. Antibody-drug conjugates (ADCs) have demonstrated marked success in a number of solid tumors, and GD2-directed drug conjugates may also hold strong therapeutic potential. In a recent study, we showed that ADCs based on the approved antibody dinutuximab and the drugs monomethyl auristatin E (MMAE) or F (MMAF) manifested potent and selective cytotoxicity in a panel of tumor cell lines and strongly inhibited solid tumor growth in GD2-positive mouse cancer models. Here, we employed two different GD2-binding moieties–minibodies and scFv fragments that carry variable antibody domains identical to those of dinutuximab, and site-directly conjugated them to MMAE or MMAF by thiol-maleimide chemistry with drug-to-antibody ratios (DAR) of 2 and 1, respectively. Specific binding of the antibody fragment-drug conjugates (FDCs) to GD2 was confirmed in direct ELISA, flow cytometry, and confocal microscopy. Selective cytotoxic and cytostatic effects of the conjugates were observed in GD2-positive but not GD2-negative neuroblastoma and melanoma cell lines. Minibody-based FDCs demonstrated more pronounced cytotoxic effects and stronger antigen binding compared to scFv-based FDCs. The developed molecules may offer considerable practical benefit, since antibody fragment-drug conjugates are capable of enhancing therapeutic efficacy of ADCs by improving their pharmacokinetic characteristics and reducing side effects.

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Section: Discussionmentioning

confidence: 99%

Minibody-Based and scFv-Based Antibody Fragment-Drug Conjugates Selectively Eliminate GD2-Positive Tumor Cells

Kalinovsky

Холоденко

Kibardin

et al. 2023

IJMS

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Killer instincts: natural killer cells as multifactorial cancer immunotherapy

Nersesian,

Carter,

Lee

et al. 2023

Front. Immunol.

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Natural killer (NK) cells integrate heterogeneous signals for activation and inhibition using germline-encoded receptors. These receptors are stochastically co-expressed, and their concurrent engagement and signaling can adjust the sensitivity of individual cells to putative targets. Against cancers, which mutate and evolve under therapeutic and immunologic pressure, the diversity for recognition provided by NK cells may be key to comprehensive cancer control. NK cells are already being trialled as adoptive cell therapy and targets for immunotherapeutic agents. However, strategies to leverage their naturally occurring diversity and agility have not yet been developed. In this review, we discuss the receptors and signaling pathways through which signals for activation or inhibition are generated in NK cells, focusing on their roles in cancer and potential as targets for immunotherapies. Finally, we consider the impacts of receptor co-expression and the potential to engage multiple pathways of NK cell reactivity to maximize the scope and strength of antitumor activities.

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GD2-targeting therapy: a comparative analysis of approaches and promising directions

Philippova,

Shevchenko,

Sennikov

2024

Front. Immunol.

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Disialoganglioside GD2 is a promising target for immunotherapy with expression primarily restricted to neuroectodermal and epithelial tumor cells. Although its role in the maintenance and repair of neural tissue is well-established, its functions during normal organism development remain understudied. Meanwhile, studies have shown that GD2 plays an important role in tumorigenesis. Its functions include proliferation, invasion, motility, and metastasis, and its high expression and ability to transform the tumor microenvironment may be associated with a malignant phenotype. Structurally, GD2 is a glycosphingolipid that is stably expressed on the surface of tumor cells, making it a suitable candidate for targeting by antibodies or chimeric antigen receptors. Based on mouse monoclonal antibodies, chimeric and humanized antibodies and their combinations with cytokines, toxins, drugs, radionuclides, nanoparticles as well as chimeric antigen receptor have been developed. Furthermore, vaccines and photoimmunotherapy are being used to treat GD2-positive tumors, and GD2 aptamers can be used for targeting. In the field of cell therapy, allogeneic immunocompetent cells are also being utilized to enhance GD2 therapy. Efforts are currently being made to optimize the chimeric antigen receptor by modifying its design or by transducing not only αβ T cells, but also γδ T cells, NK cells, NKT cells, and macrophages. In addition, immunotherapy can combine both diagnostic and therapeutic methods, allowing for early detection of disease and minimal residual disease. This review discusses each immunotherapy method and strategy, its advantages and disadvantages, and highlights future directions for GD2 therapy.

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Development of a variant of dinutuximab with enhanced antitumor efficacy and reduced induction of neuropathic pain

Cited by 3 publications

References 42 publications

Minibody-Based and scFv-Based Antibody Fragment-Drug Conjugates Selectively Eliminate GD2-Positive Tumor Cells

Minibody-Based and scFv-Based Antibody Fragment-Drug Conjugates Selectively Eliminate GD2-Positive Tumor Cells

Killer instincts: natural killer cells as multifactorial cancer immunotherapy

GD2-targeting therapy: a comparative analysis of approaches and promising directions

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