Antitumor immunity induced by antibody-based natural killer cell engager therapeutics armed with not-alpha IL-2 variant

Demaria, Olivier; Gauthier, Laurent; Vétizou, Marie; Alvarez, Audrey Blanchard; Vagne, Constance; Habif, Guillaume; Batista, Luciana; Baron, William; Belaïd, Nourhène; Girard-Madoux, Mathilde J.H.; Cesari, Cédric; Caratini, Mélody; Bosco, Frédéric; Bénac, Olivier; Lopez, Julie; Fenis, Aurore; Galluso, Justine; Trichard, Sylvia; Carrette, Barbara; Carrette, Florent; Maguer, Aurélie; Jaubert, Solène; Sansaloni, Audrey; Letay-Drouet, Robin; Kosthowa, Camille; Lovera, Naouel; Dujardin, Arnaud; Chanuc, Fabien; Van, Mélanie Le; Bokobza, Sivan M.; Jarmuzynski, Nicolas; Fos, Camille; Gourdin, Nicolas; Remark, Romain; Lechevallier, É.; Fakhry, Nicolas; Salas, Sébastien; Deville, Jean‐Laurent; Grand, Roger Le; Bonnafous, Cécile; Vollmy, Lukas; Représa, Agnès; Carpentier, Sabrina; Rossi, Benjamín; Morel, Ariane; Cornen, Stéphanie; Perrot, Ivan; Morel, Yannis; Vivier, Éric

doi:10.1016/j.xcrm.2022.100783

Cited by 41 publications

(31 citation statements)

References 51 publications

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“…NKp30 is another activating receptor on NK cells belonging to the group of NCRs (Pende et al, 1999). In contrast to NKp46, the expression of NKp30 on tumor infiltrating NK cells is downregulated while it is more consistently expressed on NK cells in the blood of cancer patients (Demaria et al, 2022). Moreover, NKp30 is also displayed by other immune cell subsets that might be beneficial in therapeutic settings (Correia et al, 2018; Hudspeth et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

NKp46‐specific single domain antibodies enable facile engineering of various potent NK cell engager formats

et al. 2023

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Herein, we describe the generation of potent NK cell engagers (NKCEs) based on single domain antibodies (sdAbs) specific for NKp46 harboring the humanized Fab version of Cetuximab for tumor targeting. After immunization of camelids, a plethora of different VHH domains were retrieved by yeast surface display. Upon reformatting into Fc effector-silenced NKCEs targeting NKp46 and EGFR in a strictly monovalent fashion, the resulting bispecific antibodies elicited potent NK cell-mediated killing of EGFR-overexpressing tumor cells with potencies (EC 50 killing) in the picomolar range. This was further augmented via co-engagement of Fcγ receptor IIIa (FcγRIIIa). Importantly, NKp46-specific sdAbs enabled the construction of various NKCE formats with different geometries and valencies which displayed favorable biophysical and biochemical properties without further optimization. By this means, killing capacities were further improved significantly. Hence, NKp46-specific sdAbs are versatile building blocks for the construction of different NKCE formats.

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Section: Discussionmentioning

confidence: 99%

NKp46‐specific single domain antibodies enable facile engineering of various potent NK cell engager formats

et al. 2023

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“…This ANKET comprises an IL-2v peptide activating IL-2R independently of CD25 engagement, an antibody fragment recognizing NKp46 (aNKp46-1), a Fc domain of human IgG1 interacting with Fcγ receptors, including CD16a, and a specific antibody fragment for CD20 (aCD20) as a model tumor-associated antigen. This ANKET has highly induced NK cell proliferation, antitumor cytokine release, and NKCC against different tumors in vivo (Table 2) [176]. Hence, ANKETs specifically targeting NK cells have a great potential in EC patients.…”

Section: Future Perspective and Conclusionmentioning

confidence: 99%

“…Hence, NK cell-derived EVs have a novel potential in cancer immunotherapeutics, including one for UCs (Table 2) [174,175]. Recently, a versatile NK cell engager platform referred as antibody-based NK cell engager therapeutics (ANKETs) has been used to generate a tetra antibody-based CD20-ANKETs (IL-2v/aNKp46/Fc/aCD20) [176,177]. This ANKET comprises an IL-2v peptide activating IL-2R independently of CD25 engagement, an antibody fragment recognizing NKp46 (aNKp46-1), a Fc domain of human IgG1 interacting with Fcγ receptors, including CD16a, and a specific antibody fragment for CD20 (aCD20) as a model tumor-associated antigen.…”

Section: Future Perspective and Conclusionmentioning

confidence: 99%

Chasing Uterine Cancer with NK Cell-Based Immunotherapies

Kumar

Bauer

Stewart

2022

Future Pharmacology

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Gynecological cancers, including endometrial adenocarcinoma, significantly contribute to cancer incidence and mortality worldwide. The immune system plays a significant role in endometrial cancer pathogenesis. NK cells, a component of innate immunity, are among the critical innate immune cells in the uterus crucial in menstruation, embryonic development, and fighting infections. NK cell number and function influence endometrial cancer development and progression. Hence, it becomes crucial to understand the role of local (uterine) NK cells in uterine cancer. Uterine NK (uNK) cells behave differently than their peripheral counterparts; for example, uNK cells are more regulated by sex hormones than peripheral NK cells. A deeper understanding of NK cells in uterine cancer may facilitate the development of NK cell-targeted therapies. This review synthesizes current knowledge on the uterine immune microenvironment and NK cell-targeted uterine cancer therapeutics.

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“…Experiments have shown that the co-engagement of CD16 and Nkp46 is more effective than CD16 and Nkp46 alone, and IL-2R can promote the proliferation of NK cells, generating a pool of NK cells that contributes to antitumor activity. CD16 Â NKp46 Â IL-2R Â CD20 induces preferential activation and proliferation of NK cells and binds to TAA to trigger cytotoxicity of NK cells, increasing cytokine and chemokine production, and there are no signs of toxicity in non-human primates [49].…”

Section: Nk Cell Engagermentioning

confidence: 99%

Trispecific antibodies for cancer immunotherapy

Yin

Wang

2023

Immunology

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Despite the clinical success of monoclonal and bispecific antibodies, there are still limitations in the therapeutic effect of malignant tumours, such as low response rate, treatment resistance, and so on, inspiring the exploration of trispecific antibodies (TsAbs). TsAbs further improve the safety and efficacy and has great clinical potential through three targets combination and formats optimization. This article reviews the development history and the target combination features of TsAbs. Although there are still great challenges in the clinical application of TsAbs, it is undeniable that TsAbs may be a breakthrough in the development of antibody drugs.

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Antitumor immunity induced by antibody-based natural killer cell engager therapeutics armed with not-alpha IL-2 variant

Cited by 41 publications

References 51 publications

NKp46‐specific single domain antibodies enable facile engineering of various potent NK cell engager formats

NKp46‐specific single domain antibodies enable facile engineering of various potent NK cell engager formats

Chasing Uterine Cancer with NK Cell-Based Immunotherapies

Trispecific antibodies for cancer immunotherapy

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