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Siplizumab Induces NK Cell Fratricide Through Antibody-Dependent Cell

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Siplizumab Induces NK Cell Fratricide Through Antibody-Dependent Cell ORIGINAL RESEARCH published: 11 February 2021 doi: 10.3389/fimmu.2021.599526 Siplizumab Induces NK Cell Fratricide Through Antibody- Dependent Cell-Mediated Cytotoxicity Christian Binder 1,2*, Felix Sellberg 1,2, Filip Cvetkovski 2, Stefan Berg 2, Erik Berglund 2,3 and David Berglund 1,2 1 Department of Immunology, Genetics and Pathology, Section of Clinical Immunology, Uppsala University, Uppsala, Sweden, 2 Research and Development, ITB-Med AB, Stockholm, Sweden, 3 Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden The glycoprotein CD2 is expressed on T and NK cells and contributes to cell-cell conjugation, agonistic signaling and actin cytoskeleton rearrangement. CD2 has Edited by: previously been shown to have an important function in natural NK cell cytotoxicity but Carsten Watzl, to be expendable in antibody-mediated cytotoxicity. Siplizumab is a monoclonal anti-CD2 Leibniz Research Centre for Working fi Environment and Human Factors IgG1 antibody that is currently undergoing clinical trials in the eld of transplantation. This (IfADo), Germany study investigated the effect of CD2 binding and Fc g receptor binding by siplizumab (Fc- Reviewed by: active) and Fc-silent anti-CD2 monoclonal antibodies in allogeneic mixed lymphocyte John Pradeep Veluchamy, reaction and autologous lymphocyte culture. Further, induction of NK cell fratricide and VU University Medical Center, Netherlands inhibition of natural cytotoxicity as well as antibody-dependent cytotoxicity by these Kerry S. Campbell, agents were assessed. Blockade of CD2 via monoclonal antibodies in the absence of Fc g Fox Chase Cancer Center, United States receptor binding inhibited NK cell activation in allogeneic mixed lymphocyte reaction. In Christian Kellner, contrast, siplizumab increased NK cell activation in both mixed lymphocyte reaction and LMU Munich University Hospital, autologous lymphocyte culture due to FcgRIIIA binding. However, experiments using Germany fi *Correspondence: puri ed NK cells did not show an inhibitory effect of CD2 blockade on natural cytotoxicity Christian Binder or antibody-dependent cytotoxicity. Lastly, it was shown that siplizumab induces NK cell [email protected] fratricide. Concluding, siplizumab is a promising biopharmaceutical drug candidate for Specialty section: depletion of T and NK cells with minimal off-target effects. This article was submitted to Keywords: NK cell, CD2, siplizumab, spontaneous cytotoxicity, antibody-dependent cell-mediated cytotoxicity, NK and Innate Lymphoid NK alloreactivity Cell Biology, a section of the journal Frontiers in Immunology Received: 27 August 2020 INTRODUCTION Accepted: 05 January 2021 Published: 11 February 2021 The glycoprotein CD2 (also known as LFA2) is expressed on T and NK cells where it serves as an Citation: adhesion and activation receptor (1). In humans, the main binding partner of CD2 is lymphocyte Binder C, Sellberg F, Cvetkovski F, associated antigen 3 (LFA3; also known as CD58) which is broadly expressed, especially on antigen- Berg S, Berglund E and Berglund D presenting cells (APCs). CD2-targeting immunotherapy is a promising treatment for organ (2021) Siplizumab Induces NK Cell Fratricide Through Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; ANOVA, analysis of variance; APC, antigen- Antibody-Dependent presenting cell; DG, deglycosylated; FcgR, Fragment crystallizable gamma receptor; FcS, Fc-silent; KIR, killer cell Cell-Mediated Cytotoxicity. immunoglobulin-like receptor; NKG2D, natural killer group 2D; HLA, human leukocyte antigen; mAb, monoclonal Front. Immunol. 12:599526. antibody; NK, natural killer; NKIS, NK cell immunological synapse; LFA3, lymphocyte-associated antigen 3; PBMC, doi: 10.3389/fimmu.2021.599526 peripheral blood mononuclear cells; RA, rheumatoid arthritis; VPD450, violet proliferation dye 450. Frontiers in Immunology | www.frontiersin.org 1 February 2021 | Volume 12 | Article 599526 Binder et al. Siplizumab Induces NK Cell Fratricide transplant recipients and patients suffering from autoimmune immunological synapse that NK cells form upon target cell diseases [Reviewed in (1)]. Siplizumab is a monoclonal anti-CD2 conjugation. While the CD2-CD58 interaction has traditionally IgG1 antibody (anti-CD2 IgG1 mAb) that is currently been known for its role in cellular adhesion, recent evidence has undergoing clinical trials in the field of transplantation demonstrated that it also plays an important role in recruiting (ClinicalTrials.gov Identifier: NCT04311632). While the potent and organizing activating receptors to the immunological in vitro immune modulatory effects of siplizumab on T cells have synapse (11, 12). been documented (2, 3), no studies published to date address the This study aimed to characterize the effects of siplizumab on in vitro effects of siplizumab on NK cells. Previous in vivo NK cell activation in mixed lymphocyte reaction (MLR) and in evidence showed siplizumab-induced peripheral T and NK cell pure NK cell culture. Further, potential effects of CD2 blockade depletion in primates (4) and human patients (5). Evidence on natural cytotoxicity and ADCC were investigated. suggests that antibody-dependent cytotoxicity is one depletory mechanism induced by siplizumab; however, the direct effects of siplizumab on NK cells remain incompletely characterized (3, 6). MATERIALS AND METHODS NK cells express activating and inhibitory receptors. The balance of signaling through both sets of receptors is integrated Generation of Fc-Silent Anti-CD2 and determines whether mature NK cells remain in a resting Antibodies state or become activated (7). Thus, NK cell activation can be Siplizumab (humanized anti-CD2 IgG1k) is an investigational elicited by a reduction of inhibitory signaling, an increase in drug and was provided by the manufacturer (ITB-Med, activation signaling, or a combination of both. Stockholm, Sweden). Among activating NK cell receptors, CD16 is one whose Deglycosylated (DG) siplizumab was produced using ® signaling can induce NK cell activation in isolation. Most GlycINATOR (EndoS2; Genovis #A0-GL1-020) according to remaining activating NK cell receptors require activation in the manufacturer’s instructions (Genovis AB, Lund, Sweden). conjunction to elicit NK cell activation. CD16a is a low affinity Fc-silent (FcS) anti-CD2 mAbs were generated via Fc g receptor (FcgR) and is also known as FcgRIIIA. NK cell introduction of amino acid substitutions into the sequence of binding to target-bound IgG antibodies via CD16a promotes siplizumab or standard IgG2/IgG4 frameworks. All Fc-silent antibody-dependent cell-mediated cytotoxicity (ADCC). Other antibodies had identical light chains and complementarity- activating NK cell receptors include NKG2D, certain killer cell determining regions and were produced by Wuxi Biologics immunoglobulin-like receptors (KIRs) and NKp46 which bind to Limited (Wuxi, China). Genetic sequences for each antibody tumor antigens, foreign HLA and viral proteins, respectively. were cloned into plasmids followed by transient transfection Most prominent among inhibitory NK cell receptors are KIRs and production in Chinese hamster ovary (CHO-K1) cells. which recognize self-HLA (8). Antibody-independent target cell Anti-CD2 mAbs were purified using protein A and IEX/SEC killing by NK cells is commonly termed natural or spontaneous columns to at least 95% purity and endotoxin levels below 1 NK cell cytotoxicity. In addition to FcgRIIIA, certain NK cell EU/mg. Fc-silent siplizumab (FcS anti-CD2 IgG1) was subsets can express two forms of CD32/FcgRII, FcgRIIB, and generated by introducing the commonly known LALA-PG FcgRIIC (9). mutations to equivalent sites in siplizumab (13, 14). FcS anti- A critical event preceding NK cell cytotoxicity is stable target CD2 IgG2 was generated by introducing the following cell conjugation via cell-cell adhesion molecules (10). Once stable mutations at equivalent sites in a standard IgG2 framework: target cell conjugation has occurred and the NK cell V234A, G237A P238S, H268A, V309L, A330S, P331S (15). FcS immunological synapse (NKIS) has formed, actin cytoskeleton anti-CD2 IgG4 was generated by introducing the following rearrangement proceeds to facilitate transport of lytic vesicles to mutations at equivalent sites in a standard IgG4 framework: the NKIS and subsequent release to achieve target cell killing. S228P, L235E, P329G (16, 17). Examples of adhesion molecules involved in NK-target cell conjugation and NKIS formation are LFA-1 (8) and CD2 (10) Surface Plasmon Resonance CD2 Binding binding to ICAM-1 and LFA3 on the target cell, respectively. Interaction experiments were performed using a Biacore T200 Even in natural NK cell cytotoxicity CD16 is enriched in the instrument (Cytiva Life Sciences/Biacore, Uppsala, Sweden). NKIS through interaction with CD2. Abrogation of this IgG was immobilized to a surface density of 200-1300 RU interaction between CD2 and CD16 markedly decreases using standard amine coupling and CM5 biosensor chips natural NK cell cytotoxicity but does not affect NK-mediated (Cytiva Life Sciences/Biacore, Uppsala, Sweden) with a 10 mM ADCC (11). CD2 has two Ig domains, one membrane distal HEPES buffer at pH 7.4, with 150 mM NaCl, 0.5 mM EDTA, domain and one membrane proximal domain. The membrane 0.05% Tween20 running buffer. Each antibody was immobilized distal domain binds LFA3 but to date the site on CD2 which
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