(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property llllllllllllllllllllllllllllllll^ Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/077926 Al 03 May 2018 (03.05.2018) WIPO I PCT (51) International Patent Classification: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, C07K16/28 (2006.01) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (21) International Application Number: (84) Designated States (unless otherwise indicated, for every PCT/EP2017/077261 kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (22) International Filing Date: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 25 October 2017 (25.10.2017) TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (25) Filing Language: English EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (26) Publication Language: English TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (30) Priority Data: KM, ML, MR, NE, SN, TD, TG). 16306392.8 25 October 2016 (25.10.2016) EP Published: (71) Applicants: INSERM (INSTITUT NATIONAL DE — with international search report (Art. 21(3)) LA SANTE ET DE LA RECHERCHE MEDICALE) — with sequence listing part of description (Rule 5.2(a)) [FR/FR]; 101, rue de Tolbiac, 75013 Paris (FR). UNIVERSITE PARIS DIDEROT - PARIS 7 [FR/FR]; 5, rue Thomas Mann, 75013 Paris (FR). UNIVERSITE DE MONTPELLIER [FR/FR]; 163, rue Auguste Broussonnet, 34090 Montpellier (FR). INSTITUT JEAN GODINOT = [FR/FR]; 1 RUE DU GENERAL KOENIG, 51100 REIMS (FR). INSTITUT REGIONAL DU CANCER DE __ MONTPELLIER [FR/FR]; 208, Rue Des Apothicaires - == Parc Euromedecine, 34298 Montpellier (FR). (72) Inventors: BENSUSSAN, Armand; U976 - Hopital Saint Louis, 1 Avenue Claude Vellefaux - Pavilion Bazin, 75010 Paris (FR). ROBERT, Bruno; U1194 / ~~ IRCM, 208, rue des Apothicaires, 34298 MONTPEL­ LIER (FR). MARTINEAU, Pierre; U1194 / IRCM, 208, rue des Apothicaires, 34298 MONTPELLIER Cedex 5 (FR). CHENTOUF, Myriam; U1194 / IRCM, 208 rue des Apothicaires, 34298 MONTPELLIER Cedex 5 (FR). MARIE-CARDINE, Anne; HOPITAL SAINT LOUIS - ΞΞ INSERM U976 1 avenue Claude Vellefaux, 75010 PARIS (FR)· GUSTINIANI, Jerome; EA7319 / Universite de Reims Champagne-Ardenne, 9 Boulevard de la Paix, 51100 ΞΞ REIMS (FR). ~~ (74) Agent: COLLIN, Matthieu; Inserm Transfert, 7 rue Watt, 75013 PARIS (FR). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, Al MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (54) Title: MONOCLONAL ANTIBODIES BINDING TO THE CD 160 TRANSMEMBRANE ISOFORM (57) Abstract: The present invention relates to monoclonal antibodies that bind to the CD160-TM isoform. The inventors developed new monoclonal antibodies which bind to the CD160-TM isoform but dot not bind to the CD 160 GPI-anchored isoform not to the 2018/077926 CD 160 soluble isoform.In particular, the antibodies of the present invention are suitable for amplifying NK cell activation and therefore cytotoxic functions NK cells. WO WO 2018/077926 PCT/EP2017/077261 MONOCLONAL ANTIBODIES BINDING TO THE CD160 TRANSMEMBRANE ISOFORM 5 FIELD OF THE INVENTION: The present invention relates to antibodies (preferably monoclonal antibodies) binding to the CD160-TM isoform. BACKGROUND OF THE INVENTION: 10 CD 160 has been initially identified as a GPI-anchored (CD160-GPI) MHC-class I activating receptor mainly expressed on peripheral blood NK cells. It was additionally reported the identification of a CDf60 transmembrane isoform (CDf60-TM) resulting from the alternative splicing of CD 160 gene. It was established that CD160-TM surface expression is highly restricted to NK cells and is activation-dependent (Giustiniani J et al. J Immunol. 2009 15 Jan 1; 182(1):63-71). Indeed, CD160-TM is only expressed by activated NK cells, whereas CD160-GPI is expressed by NK cells (activated or not) and by different subsets of T cells. In addition, it was provided evidences that CD160-TM represent a novel activating receptor, as assessed by the increased CD 107a NK cell surface mobilization observed upon its engagement (Giustiniani J et al. 2009). 20 Accordingly, antibodies that bind to the CD160-TM isoform without binding to the CD 160 GPI-anchored isoform nor to the CD 160 soluble isoform that may result from the proteolytic cleavage of the CD 160-GPI isoform can thus be suitable, for example for amplifying NK cell activation and therefore effector functions of NK cells (cytotoxicity, cytokine secretion etc.) or for inducing depletion of CD160-TM expressing cells (in particular activated NK cells) 25 in vivo. In particular, using an antibody capable of binding to the CD160-TM isoform but not to the CD 160-GPI iso form will avoid any systemic toxicity such as cytokine storm risk. W02008/009711 describes antibody CL1-R2, an IgGl capable of binding CD160-GPI. Giustiniani J. et al. (Curr Mol Med. 2012 Feb;12(2):188-98.) describes a monoclonal antibody that binds to the CD160-TM isoform. However, this antibody also binds the soluble 30 isoform of CD 160. W02008/155363 describes the production of polyclonal antibodies directed to CD 160- TM but not binding to the CD 160-GPI isoform. These antibodies were obtained by immunizing rabbits with a peptide (peptide 2) comprising amino acids 144-158 of CD160-TM (KQRQHLEFSHNNEGTL, SEQ ID NO: 32). 1 WO 2018/077926 PCT/EP2017/077261 In the present invention, the Inventors developed a novel antibody binding to the CD160-TM isoform, but not to the CD160-GPI or to the soluble CD 160 isoforms. SUMMARY OF THE INVENTION: 5 The present invention relates to human antibodies (preferably monoclonal antibodies) binding to the CD160-TM iso form. In particular, the present invention is defined by the claims. In particular, the present invention relates to a monoclonal antibody which binds to the extracellular domain of the CD160-TM isoform, wherein said antibody does not bind to the GPI-anchored isoform nor to the CD 160 soluble isoform, and wherein the epitope of said 10 monoclonal antibody comprises at least one amino acid residue from amino acid residues 175 to 189 of SEQ ID NO: 1. In one embodiment, said epitope further comprises at least one amino acid residue from amino acid residues 62 to 85 of SEQ ID NO: 1. In one embodiment, the monoclonal antibody of the invention is a chimeric antibody, a 15 humanized antibody or a human antibody. In one embodiment, the monoclonal antibody of the invention comprises a light chain comprising at least one of the following CDR: i) the VL-CDR1 as set forth in SEQ ID NO: 6 wherein Xu is Y or S and X12 is G or Y, ii) the VL-CDR2 as set forth in SEQ ID NO: 7 and iii) the VL-CDR3 as set forth in SEQ ID NO: 8 wherein X3 is S or Y, and/or a heavy chain 20 comprising at least one of the following CDR i) the VH-CDR1 as set forth in SEQ ID NO: 9 wherein X3 is S or Y, ii) the VH-CDR2 as set forth in SEQ ID NO: 10 wherein Xi is Y or G and X10 is N or S and iii) the VH-CDR3 as set forth in SEQ ID NO: 11. In one embodiment, the monoclonal antibody of the invention comprises a light chain comprising the following CDR: i) the VL-CDR1 as set forth in SEQ ID NO: 6 wherein X11 is 25 Y or S and X12 is G or Y, ii) the VL-CDR2 as set forth in SEQ ID NO: 7 and iii) the VL-CDR3 as set forth in SEQ ID NO: 8 wherein X3 is S or Y, and a heavy chain comprising the following CDR i) the VH-CDR1 as set forth in SEQ ID NO: 9 wherein X3 is S or Y, ii) the VH-CDR2 as set forth in SEQ ID NO: 10 wherein Xi is Y or G and X10 is N or S and iii) the VH-CDR3 as set forth in SEQ ID NO: 11. 30 In one embodiment, the monoclonal antibody of the invention comprises a light chain comprising the following CDR: i) VL-CDR1: AGTSSDVGGYYGVS (SEQ ID NO: 20), ii) VL-CDR2: YDSYRPS (SEQ ID NO: 7) and iii) VL-CDR3: SSSTYYSTRV (SEQ ID NO: 24), and the heavy chain of the A12 antibody comprises the following CDR i) VH-CDR1: NYSMN 2 WO 2018/077926 PCT/EP2017/077261 (SEQ ID NO: 26), ii) VH-CDR2: YIYGSSRYISYADFVKG (SEQ ID NO: 29) and iii) VH- CDR3: GMDV (SEQ ID NO: 11). In one embodiment, the monoclonal antibody of the invention comprises a light chain comprising the following CDR: i) VL-CDR1: AGTSSDVGGYSYVS (SEQ ID NO: 23), ii) 5 VL-CDR2: YDSYRPS (SEQ ID NO: 7) and iii) VL-CDR3: SSYTYYSTRV (SEQ ID NO: 25), and the heavy chain of the A12 antibody comprises the following CDR i) VH-CDR1: NYYMN (SEQ ID NO: 27), ii) VH-CDR2: GIYGSSRYINYADFVKG (SEQ ID NO: 30) and iii) VH- CDR3: GMDV (SEQ ID NO: 11).