Compositions and methods for treating autoimmune diseases and cancer by targeting IGSF8

Abstract

The present invention provides methods and compositions for treating cancer and / or autoimmune diseases by modulating the expression and / or activity of IGSF8 and its binding ligand. The pharmaceutical compositions include, but are not limited to, antibodies that specifically bind to human IGSF8 and have activity of inhibiting IGSF8-mediated immunosuppression in a subject in need thereof. The pharmaceutical compositions may include, but are not limited to, antibodies that specifically bind to human IGSF8 and have activity of inhibiting IGSF8-mediated immunosuppression in a subject in need thereof.

Description

[Technical Field]

[0001] This international patent application claims priority to International Patent Application No. PCT / CN2021 / 111469, filed August 9, 2021, the entire contents of which, including all figures and sequences, are incorporated herein by reference.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy, created on August 9, 2022, is named 134325-01120_SL.txt and is 476,230 bytes in size. [Background technology]

[0003] IGSF8 (Immunoglobulin Superfamily Member 8, also known as EWI-2, CD316, and numerous other names) encodes a 613 amino acid (or 65 kDa) protein that is a member of the EWI subfamily of the immunoglobulin protein superfamily. This subfamily contains a transmembrane domain, an EWI (Glu-Trp-Ile) motif (hence the EWI subfamily), and a variable number of immunoglobulin domains.

[0004] The human and mouse IGSF8 protein sequences share 91% sequence identity. IGSF8 transcripts in both species are expressed in almost all tissues examined, yet little is known about the biological function of IGSF8. IGSF8 has been reported to interact specifically and directly with the tetraspanins CD81 and CD9, but not with other tetraspanins or integrins, suggesting that it may regulate the role of CD9 and CD81 in certain cellular functions, such as cell migration and viral infection (Stipp et al., J. Biol. Chem. 276(44):40545-40554, 2001). IGSF8 has also been found to directly interact with another tetraspanin, KAI1 / CD82, a tumor metastasis suppressor, identifying it as a potential tumor suppressor. It has been speculated that IGSF8 may be important or necessary for KAI1 / CD82-mediated inhibition of cancer cell migration (Zhang et al., Cancer Res. 63(10):2665-2674, 2003). IGSF8 has also been found to bind to the integrin α4β1 from MOLT-4 T leukemia cells, and IGSF8-dependent reorganization of the α4β1-CD81 complex on the cell surface has been suggested to be involved in IGSF8 effects on integrin-dependent morphology and motility (Kolesnikova et al., Blood 103(8):3013-3019, 2004). Finally, IGSF8 has been found to regulate α3β1 integrin-dependent cell functions on laminin-5 (Stipp et al., JCB 163(5):1167-1177, 2003).

[0005] For example, checkpoint-based immunotherapies using anti-CTLA-4 and anti-PD-1 / PD-L1 antibodies have shown remarkable clinical benefits in many patients, but a large proportion of cancer patients still do not respond to these treatments. Researchers are trying to understand why such T cell-based immunotherapies are ineffective in these so-called "non-responders."

[0006] Tumors can evade T cell-mediated immunity by downregulating the expression of major histocompatibility complex class I (MHC-I) molecules. Partial or complete loss of MHC-I expression on the surface of cancer cells has been demonstrated to be a major mechanism of acquired resistance to certain T cell-based immunotherapies. More importantly, approximately 40% of cancer patients who have acquired resistance to anti-PD-1 / PD-L1 or CTLA4 immunotherapy exhibited complete loss of MHC-I expression on their cancer cells. These tumors are "immune inactive" tumors and, unfortunately, comprise more than 70% of all tumors in cancer patients.

[0007] Although MHC-I-deficient tumor cells can, at least theoretically, completely evade killing by T cells, they remain susceptible to destruction by natural killer (NK) cells of the innate immune system. However, in the tumor microenvironment (TME), for reasons that are not yet fully understood, most NK cells are inactivated and are unable to specifically recognize and kill cancer cells that do not express MHC-I.

[0008] On the other hand, certain immunosuppressive receptors (e.g., NKG2A, PD-1, LAG-3, TIGIT, and TIM-3) have been found to be expressed on both effector T and NK cells. Several monoclonal antibodies against these targets can reverse the functional exhaustion of NK cells within tumors, raising hopes that NK cell-based cancer immunotherapy could complement the limitations of T cell-based immunotherapy. However, almost all of the ligands on cancer cells identified to suppress NK cell activity in the tumor microenvironment are HLA ligands, and these are highly variable between individuals and unrelated individuals, raising doubts that this strategy may not be generally applicable to larger patient populations. Meanwhile, few non-HLA ligands on cancer cells that can suppress NK cell activity in the tumor microenvironment have been identified. Summary of the Invention

[0009] Therefore, to advance NK cell-based cancer immunotherapy, there remains a need to identify NK cell-inhibitory non-HLA ligands that may be hijacked by cancer cells to evade NK cell-mediated killing in the tumor microenvironment, as well as reagents that can block NK cell suppression.

[0010] One aspect of the present invention provides an isolated or recombinant monoclonal antibody or antigen-binding fragment thereof specific for IGSF8 (e.g., specific for the Ig-V set domain or D1 domain of the ECD of IGSF8), wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising VH CDR1, VH CDR2, and VH CDR3, and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3: (1) the VH CDR1, VH CDR2, and VH CDR3 comprise, consist essentially of, or consist of the VH CDR1, VH CDR2, and VH CDR3, respectively, of antibody L1-23; and (2) the VL CDR1, VL CDR2, and VL CDR3 comprise, consist essentially of, or consist of the VL CDR1, VL CDR2, and VL CDR3, respectively, of antibody L1-23.

[0011] In certain embodiments, (1) VH CDR1, VH CDR2, and VH CDR3 comprise, consist essentially of, or consist of GFTFSTYG (SEQ ID NO: 601), IWDDGSYK (SEQ ID NO: 602), and ARDGSGWGYAFDI (SEQ ID NO: 605), respectively; and (2) VL CDR1, VL CDR2, and VL CDR3 comprise, consist essentially of, or consist of QDIGPW (SEQ ID NO: 614), GSP (SEQ ID NO: 625), and QQYDSFPYT (SEQ ID NO: 631), respectively.

[0012] In certain embodiments, (1) the VH comprises VH FR1, VH FR2, VH FR3, and / or VH FR4, each of which comprises QVQLVESGGGVVQPGRSLRLSCAAS (SEQ ID NO: 606), or an amino acid sequence having at most 1, 2, 3, 4, or 5 substitutions, deletions, and / or additions thereof; MHWVRQAPGKGLEWVAV (SEQ ID NO: 607), or an amino acid sequence having at most 1, 2, 3, 4, or 5 substitutions, deletions, and / or additions thereof; YYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC (SEQ ID NO: 608), or an amino acid sequence having at most 1, 2, 3, 4, or 5 substitutions, deletions, and / or additions thereof; and WGQGTLVTVSS (SEQ ID NO: 610), or an amino acid sequence having at most 1, 2, 3, 4, or 5 substitutions, deletions, and / or additions thereof. and (2) VL comprises VL FR1, VL FR2, VL FR3, and / or VL FR4 that respectively comprise DIQLTQSPSSLSASVGDRVTITCQAS (SEQ ID NO: 632), or an amino acid sequence having at most 1, 2, 3, 4, or 5 substitutions, deletions, and / or additions thereof, LNWYQHKPGKAPKPLVF (SEQ ID NO: 637), or an amino acid sequence having at most 1, 2, 3, 4, or 5 substitutions, deletions, and / or additions thereof, NLETGVPSRFSASGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 640), or an amino acid sequence having at most 1, 2, 3, 4, or 5 substitutions, deletions, and / or additions thereof, and FGQGTKVEIK (SEQ ID NO: 642), or an amino acid sequence having at most 1, 2, 3, 4, or 5 substitutions, deletions, and / or additions thereof.

[0013] In specific embodiments, (1) the VH comprises the amino acid sequence of the VH sequence of antibody L1-23 (SEQ ID NO: 670), or an amino acid sequence having the same VH CDR sequence and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity in the framework regions of SEQ ID NO: 670; and (2) the VH comprises the amino acid sequence of the VL sequence of antibody L1-23 (SEQ ID NO: 694), or an amino acid sequence having the same VH CDR sequence and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity in the framework regions of SEQ ID NO: 694.

[0014] In a specific embodiment, the VH and VL sequences comprise the amino acid sequences of SEQ ID NOs: 670 and 694, respectively.

[0015] In certain embodiments, the monoclonal antibody or antigen-binding fragment thereof of the invention is a human-mouse chimeric antibody, a humanized antibody, a human antibody, a CDR-grafted antibody, or a resurfaced antibody.

[0016] In certain embodiments, the antigen-binding fragment is a Fab, Fab', F(ab'), F d , single-chain Fv or scFv, disulfide-linked F v , V-NAR domain, IgNar, intrabody, IgGΔCH2, minibody, F(ab')3, tetrabody, triabody, diabody, single domain antibody, DVD-Ig, Fcab, mAb2, (scFv)2, or scFv-Fc.

[0017] In certain embodiments, the monoclonal antibody or antigen-binding fragment thereof of the present invention comprises a heavy chain constant region, wherein (a) the heavy chain constant region is wild-type human IgG1, human IgG2, human IgG3, or human IgG4; or (b) the heavy chain constant region has an Fc domain that is deficient in antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and / or antibody-dependent cellular phagocytosis (ADCP).

[0018] In certain embodiments, the heavy chain constant region having a missing Fc domain is selected from the group consisting of IgG1-L234A / L235A (IgG1-LALA), IgG1-L234A / L235A / P329G (IgG1-LALA-PG), IgG1-N297A / Q / G (IgG1-NA), IgG1-L235A / G237A / E318A (IgG1-AAA), IgG1-G236R / L328R (IgG1-RR), IgG1-S298G / T299A (IgG1-GA), IgG1-L234F / L235E / P331S (IgG1- FES), IgG1-L234F / L235E / D265A (IgG1-FEA), IgG4-L234A / L235A (IgG4-LALA), IgG4-S228P / L235E (IgG4-PE), IgG1-E233P / L234V / L235A / G236del / S267K, IgG2-H268Q / V309L / A30S / P331S (IgG2m4), and IgG2-V234A / G237A / P238S / H268A / V309L / A330S / P331S (IgG2c4d).

[0019] In certain embodiments, the monoclonal antibody or antigen-binding fragment thereof has a K of less than about 25 nM, 20 nM, 15 nM, 10 nM, 5 nM, 2 nM, or 1 nM. d It binds to IGSF8.

[0020] Another aspect of the present invention provides polynucleotides encoding the monoclonal antibodies of the present invention, their heavy or light chains, or antigen-binding sites / fragments thereof.

[0021] Another aspect of the present invention provides polynucleotides that hybridize under stringent conditions to the polynucleotides of the present invention or to the complements of the polynucleotides of the present invention.

[0022] Another aspect of the present invention provides a vector comprising a polynucleotide of the present invention.

[0023] Another aspect of the invention provides a host cell comprising a polynucleotide of the invention, or a vector of the invention, for expressing the encoded monoclonal antibody, its heavy or light chain, or antigen-binding portion / fragment thereof.

[0024] Another aspect of the present invention provides a method for producing a monoclonal antibody of the present invention, its heavy or light chain, or antigen-binding site / fragment thereof, comprising the steps of: (i) culturing a host cell according to claim 14 capable of expressing said monoclonal antibody, its heavy or light chain, or antigen-binding site / fragment thereof under conditions suitable for expressing said monoclonal antibody, its heavy or light chain, or antigen-binding site / fragment thereof; and, optionally, (ii) recovering / isolating / purifying the expressed monoclonal antibody, its heavy or light chain, or antigen-binding site / fragment thereof.

[0025] Another aspect of the present invention provides a method for modulating an immune response in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention.

[0026] Another aspect of the present invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention.

[0027] In certain embodiments, the method further comprises administering to the subject an effective amount of a second therapeutic agent comprising an immunotherapeutic agent, an immune checkpoint inhibitor, a cancer vaccine, a chimeric antigen receptor, a chemotherapeutic agent, a radiotherapeutic agent, an anti-angiogenic agent, a growth inhibitory agent, an immuno-oncology agent, an anti-neoplastic composition, surgery, or a combination thereof.

[0028] In certain embodiments, the anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof is conjugated to a cytotoxic agent.

[0029] In certain embodiments, the cytotoxic agent is selected from the group consisting of a chemotherapeutic agent, a biologic agent, a toxin, and a radioisotope.

[0030] In certain embodiments, the anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof reduces the number of cells proliferating in the cancer and / or reduces the volume or size of the cancer tumor.

[0031] In certain embodiments, the anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof is administered in a pharmaceutically acceptable formulation.

[0032] In certain embodiments, the cancer is melanoma (including cutaneous melanoma), cervical cancer, lung cancer (e.g., non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma), colorectal cancer, lymphoma (including B-cell lymphoma and DLBCL), leukemia (including CLL and acute myeloid leukemia (AML)), BLCA tumors, breast cancer, head and neck cancer, head and neck squamous cell carcinoma, PRAD, THCA, or UCEC, thyroid cancer, unit duct carcinoma, uterine cancer, esophageal cancer, liver cancer, ganglionic carcinoma, kidney cancer, pancreatic cancer, pancreatic ductal carcinoma, ovarian cancer, prostate cancer, glioma, glioblastoma, neuroblastoma, thymoma, B-CLL, and cancers infiltrated with immune cells expressing receptors for IGSF8.

[0033] In certain embodiments, the cancer is lung cancer, kidney cancer, pancreatic cancer, colorectal cancer, acute myeloid leukemia (AML), head and neck cancer, liver cancer, ovarian cancer, prostate cancer, or uterine cancer.

[0034] In certain embodiments, cancer cells and / or tumor immune infiltrating cells in a subject express IGSF8.

[0035] In certain embodiments, the anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof stimulates the activation and / or infiltration of T cells and / or NK cells into the tumor microenvironment.

[0036] In certain embodiments, the immune checkpoint inhibitor is an antibody or antigen-binding fragment thereof specific for PD-1, PD-L1, PD-L2, LAG3, TIGIT, TIM3, NKG2A, CD276, VTCN1, VISR, or HHLA2.

[0037] In certain embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody, such as cemipillimab, nivolumab, or pembrolizumab.

[0038] In certain embodiments, the immune checkpoint inhibitor is an anti-PD-L1 antibody, such as avelumab, durvalumab, atezolizumab, KN035, or CK-301.

[0039] In certain embodiments, the immune checkpoint inhibitor is a (non-antibody) peptide inhibitor of PD-1 / PD-L1, such as AUNP12; a small molecule inhibitor of PD-L1, such as CA-170; or a macrocyclic peptide, such as BMS-986189. In certain embodiments, the second therapeutic agent is selected from the group consisting of, for example, 3F8, 8H9, abagovomab, abciximab, abituzumab, abrezekimab, abrilumab, actoxumab, adalimumab, adecatumumab, aducanumab, afacevicumab, afelimomab, alacizumab pegol, alemtuzumab, alirocumab, altumomab pentetate, amatuximab, amivantamab, anatumomab mafenatox, andecaliximab, anetumab ravtansine, anifrolumab, anrukinzumab, apolizumab, aprilumab ixadotin, andarutumomab. Mab, asclinical steroids, ascelizumab, atezolizumab, atidortoxumab, atinumab, atorolimuab, avelumab, azintuximab vedotin, bapineuzumab, basiliximab, bavituximab, BCD-100, bectumomab, begelomab, belantamab mafodotin, belimumab, bemarituzumab, benralizumab, berlimatoxumab, bermekimab, bersanlimab, bertilimumab, besilesomab, bevacizumab, bezlotoxumab, biciromab, bimagrumab, bimekizumab, vilutamimab, bivatuzumab, bleselumab, Linatumomab, brontuzumab, brosozumab, bococizumab, brazikumab, brentuximab vedotin, briakinumab, brodalumab, brolucizumab, brontuximab, burosumab, cabilalizumab, camidanlumab tesirin, camrelizumab, canakinumab, cantuzumab mertansine, cantuzumab ravtansine, caplacizumab, capromab, carlumab, carotuximab, catumaxomab, cBR-doxorubicin immunoconjugate, cedelizumab, cemiplimab, sergituzumab amnaleukin, certolizumab pegol, se Tolerimab, cetuximab, civisatamab, cimutuzumab, sitatuzumab bogatox, cixutumumab, clazakizumab, clenoliximab, clivatuzumab tetraxetan, codrituzumab, cofetuzumab peridotin, coltuximab ravtansine, conatumumab, concizumab, cosfrobiximab, crenezumab, crizanlizumab, clotedumab, CR6261, cusatuzumab, dacetuzumab, daclizumab, dalotuzumab, dapirolizumab pegol, daratumumab, dectrecumab, demcizumab, denituzumab mafodotin, denosumab,Depatuxizumab mafodotin, dellotuximab biotin, detumomab, dezamizumab, dinutuximab, zilidabumab, domagurozumab, dorlimomab alitox, dostarlimab, drozitumab, DS-8201, durigotuzumab, dupilumab, durvalumab, dusigitumab, duvortuxizumab, ecromeximab, eculizumab, edovacomab, edrecolomab, efalizumab, efangumab, eldelumab, elezanumab, elgemtumab, elotuzumab, ersilimomab, emactuzumab, emapalumab, emibetuzumab, emi Cizumab, enapotamab vedotin, enavatuzumab, enfortumab vedotin, enlimomab pegol, enoblitzumab, enokizumab, enoticumab, encituximab, epitumomab cituxetan, epratuzumab, eptinezumab, erenumab, erlizumab, ertumaxomab, etaracizumab, etigilimab, etrolizumab, evinacumab, evolocumab, exbivirumab, fanolesomab, faralimomab, faricimab, farletuzumab, fasinumab, FBTA05, felvizumab, fezakinumab, fivatuzumab, ficratuzumab Ibuprofen, figitumumab, filibumab, framvotumab, fretikumab, flotetuzumab, fontolizumab, foralumab, foravirumab, fremanezumab, fresolimumab, frobocimab, furovetomab, furunevetumab, furanumab, futuximab, galcanezumab, galiximab, gancotamab, ganitumab, gantenerumab, gatipotuzumab, gavirimomab, gezivumab, gemtuzumab ozogamicin, gevokizumab, zirvetumab, dimcirumab, dilentuximab, glenbatumumab vedotin, golimumab, gomiliximab, goslanemab, guselk Mab, ranalumab, ibalizumab, IBI308, ibritumomab tiuxetan, icrucumab, idarucizumab, ifavotuzumab, igovomab, iradatuzumab vedotin, IMAB363, imalumab, imaprelimab, imciromab, imgatuzumab, inlacumab, indatuximab vedotin, inebilizumab, infliximab, intetumumab, inolimomab, inotuzumab ozogamicin, ipilimumab, Iomab-B, iratumumab, isatuximab, iscalimab, istiratumab, itolizumab,Ixekizumab, keliximab, labetuzumab, lacnotuzumab, radlatuzumab vedotin, lampalizumab, lanadelumab, landgrozumab, laprituximab emtansine, ralcabiximab, lebrikizumab, remaresomab, lendalizumab, lembervimab, lenzilumab, lerdelimumab, leronlimab, lesofabumab, letolizumab, lexatumumab, ribivirumab, rifastuzumab vedotin, ligelizumab, loncustuximab tecilline, rosatuximab vedotin, rilotrazole, rilostuzumab, rilostuzumab vedotin, rilostuzumab septin ... Delucizumab, loxivetumab, lorvotuzumab mertansine, lucatumumab, lurizumab pegol, lumiliximab, lumuletuzumab, rupartumab, rupartumab amadotin, rutikizumab, mapatumumab, marjetuximab, marstacimab, maslimomab, mavrilimumab, matuzumab, mepolizumab, metelimumab, milatuzumab, minletumomab, mirikizumab, mirvetuximab soravtansine, mitumomab, modotuximab, mogamulizumab, monalizumab, morolimumab, mosunetuzumab, motavizumab, moxetumomab pasudotoxin, Muromonab-CD3, nacolomabutafenatox, namilumab, naptumomab estafenatox, naratuximab emtansine, narutumab, natalizumab, navicixizumab, navivumab, naxitamab, nebacumab, necitumumab, nemolizumab, NEOD001, nerelimomab, nesbacumab, netakimab, nimotuzumab, nirsevimab, nivolumab, nofetumomab merpentane, obilutoxaximab, obinutuzumab, occaratuzumab, ocrelizumab, odulimomab, ofatumumab, olaratumumab, olecurumab, orendalizumab , olokizumab, omalizumab, omburtamab, OMS721, onartuzumab, ontuxizumab, onvatilimab, opicinumab, oportuzumab monatox, oregovomab, olticumab, otelixizumab, otilimab, otlertuzumab, oxelumab, ozoralizumab, pasivaximab, palivizumab, pamrevlumab, panitumumab, pancomab, panobacumab, palsatuzumab, pascolizumab, pasotuxizumab, pateclizumab, patritumab, PDR001, pembrolizumab, pemtumomab, perakizumabPertuzumab, pexelizumab, pidilizumab, pinatuzumab vedotin, pintumomab, placumab, prezalumab, prozalizumab, pogalizumab, polatuzumab vedotin, ponezumab, polgabiximab, prasinezumab, prezalizumab, priliximab, plitoxaximab, pritumumab, PRO140, kilimumab, racotumomab, radletumab, rafivirumab, ralpancizumab, ramucirumab, ranevetomab, ranibizumab, raxibacumab, ravagalimab, ravuturizumab, refanezumab, regavirumab, REGN-EB, relato Limab, lemtolumab, reslizumab, rilotumumab, rinukumab, risankizumab, rituximab, rivavuzumab pegol, lobatumumab, Rmab, loredumab, romilkimab, romosozumab, lontalizumab, rosmantuzumab, rovalpituzumab tesirin, rovelizumab, rozanolixizumab, ruplizumab, SA237, sacituzumab govitecan, samalizumab, samutamab vedotin, sarilumab, satralizumab, satumomab pendetide, secukinumab, selicrelumab, seribantumab, cetoxaximab, ceturusumab, sevirumab, sib Lotuzumab, SGN-CD19A, SHP647, sifalimumab, siltuximab, simtuzumab, siplizumab, siltratumab vedotin, sirukumab, sofituzumab vedotin, solanezumab, solitomab, sonepcizumab, sontuzumab, spartalizumab, stamulumab, sulesomab, sputabumab, stimulimab, subizumab, subratoxumab, tabalumab, tacatuzumab tetraxetan, tadocizumab, talacuzumab, talizumab, talquetamab, tamtubetomab, tanezumab, taplitumomab paptox, talexuzumab, tabolimab , teclistamab, tefibazumab, terimomab alitox, telisotuzumab, telisotuzumab vedotin, tenatumomab, teneliximab, teplizumab, tepositamab, teprotumumab, tesidolumab, tetulomab, tezepelumab, TGN1412, tiburizumab, tildrakizumab, tigatuzumab, timigituzumab, timolumab, tiragolumab, tiragotumab, tislelizumab, tisotuzumab vedotin, TNX-650, tocilizumab, tomzotuximab, toralizumab, tosatoxumab, tositumomab, tobetumab, tralokinumab, trastuzumab,Trastuzumab duocarmazine, trastuzumab emtansine, TRBS07, tregalizumab, tremelimumab, trevoglumab, tucotuzumab celmoleukin, tuvilumab, ublituximab, urocupulumab, urelumab, urtoxazumab, ustekinumab, utomilumab, vadastuximab butarilin, banalimab, bundlestuzumab vedotin, vanticutumab, vanucizumab, bapaliximab, valisacumab, varlilumab, batelizumab, vedolizumab, veltuzumab, vedolizumab, veltuzumab, vedotin The antibody or antigen-binding portion / fragment thereof effective for treating cancer includes, for example, palimomab, besencumab, visilizumab, bovalilizumab, volociximab, bonlerolizumab, bopratelimab, borsetuzumab mafodotin, votumumab, bunakizumab, xentuzumab, XMAB-5574, zalutumumab, zanolimumab, zatuximab, xenoctuzumab, diralimumab, zolbetuximab, (=IMAB362, claudiximab), zolimomab alitox, or a combination thereof.

[0040] In certain embodiments, the second therapeutic agent comprises an antibody or antigen-binding portion / fragment thereof that is effective to induce ADCC, ADCP and / or CDC.

[0041] In certain embodiments, the subject is an animal model of cancer.

[0042] Another aspect of the present invention provides a device or kit comprising at least one antibody, monoclonal antibody, heavy or light chain thereof, or antigen-binding site / fragment thereof of the present invention, which device or kit optionally comprises a label for detecting said at least one antibody, monoclonal antibody, heavy or light chain thereof, or antigen-binding site / fragment, or a complex comprising said at least one antibody, monoclonal antibody, heavy or light chain thereof, or antigen-binding site / fragment.

[0043] Another aspect of the present invention provides a method for detecting the presence or level of IGSF8 polypeptide in a sample, comprising contacting the IGSF8 polypeptide in the sample with an antibody, monoclonal antibody, or antigen-binding portion / fragment thereof of the present invention, wherein the antibody, monoclonal antibody, or antigen-binding portion / fragment thereof may be labeled with or attached to a detectable label.

[0044] In certain embodiments, the antibody, monoclonal antibody, or antigen-binding portion / fragment thereof forms a complex with an IGSF8 polypeptide, and the complex is detected in the form of an enzyme-linked immunosorbent assay (ELISA), a radioimmunoassay (RIA), an immunochemical method, a Western blot, or an intracellular flow assay.

[0045] Another aspect of the present invention provides a method for monitoring the progression of a disorder associated with abnormal (e.g., higher than normal) IGSF8 expression in a subject, comprising: a) detecting a first level of IGSF8 in a sample obtained from the subject at a first time point using an antibody, monoclonal antibody, or antigen-binding site / fragment of the present invention; b) repeating step a) at a subsequent time point to obtain a second level of IGSF8; and c) comparing the first and second levels of IGSF8 detected in steps a) and b), respectively, to monitor the progression of the disorder in the subject, wherein a second level higher than the first level is an indication that the disease has progressed.

[0046] In certain embodiments, between the first and subsequent time points, the subject is undergoing treatment to ameliorate the disorder.

[0047] Another aspect of the present invention provides a method of predicting the clinical outcome of a subject suffering from a disorder associated with abnormal (e.g., higher than normal) IGSF8 expression, comprising the steps of: a) determining the level of IGSF8 in a first sample obtained from the subject using an antibody, monoclonal antibody, or antigen-binding site / fragment of the present invention; b) determining the level of IGSF8 in a second sample obtained from a control subject with a good clinical outcome using the antibody, monoclonal antibody, or antigen-binding site / fragment of the present invention; and c) comparing the levels of IGSF8 in the first and second samples, wherein a significantly higher level of IGSF8 in the first sample compared to the level of IGSF8 in the second sample (e.g., a >20%, >50% or greater increase) indicates that the subject will have a worse clinical outcome, and / or a significantly lower level of IGSF8 in the first sample compared to the level of IGSF8 in the second sample (e.g., a >20%, >50% or greater decrease) is indicative of the subject having a better clinical outcome.

[0048] Another aspect of the present invention provides a method for assessing the effectiveness of a treatment for a disorder associated with abnormal (e.g., higher than normal) IGSF8 expression in a subject, comprising: a) determining the level of IGSF8 using an antibody, monoclonal antibody, or antigen-binding site / fragment of the present invention in a first sample obtained from the subject before providing at least a portion of the treatment to the subject; and b) repeating step a) in a second sample obtained from the subject after providing said portion of the treatment, wherein a significantly lower level of IGSF8 in the second sample compared to the first sample (a decrease of >20%, >50% or more) indicates that the treatment is effective in inhibiting the disorder in the subject; and / or a substantially identical or higher level of IGSF8 in the second sample compared to the first sample is an indication that the treatment is not effective in inhibiting the disorder in the subject.

[0049] In certain embodiments, the disease is cancer.

[0050] Another aspect of the present invention provides a method for assessing the effectiveness of a test compound for inhibiting a disorder associated with abnormal (e.g., higher than normal) IGSF8 expression in a subject, comprising the steps of: a) determining the level of IGSF8 in a first sample obtained from the subject using an antibody, monoclonal antibody, or antigen-binding site / fragment of the present invention, wherein the first sample has been exposed to an amount of the test compound; and b) determining the level of IGSF8 in a second sample obtained from the subject using the antibody, monoclonal antibody, or antigen-binding site / fragment of the present invention, wherein the second sample has not been exposed to the test compound, wherein a significantly lower IGSF8 level (a decrease of >20%, >50% or more) in the first sample compared to the second sample is an indication that the amount of the test compound is effective in inhibiting the disorder in the subject, and / or a substantially identical level of IGSF8 in the first sample compared to the second sample is an indication that the amount of the test compound is not effective in inhibiting the disorder in the subject.

[0051] In certain embodiments, the first and second samples are part of a single sample obtained from the subject or part of pooled samples obtained from the subject.

[0052] In certain embodiments, the disorder is cancer.

[0053] In certain embodiments, the cancer is lung cancer, kidney cancer, pancreatic cancer, colorectal cancer, acute myeloid leukemia (AML), head and neck cancer, liver cancer, ovarian cancer, prostate cancer, uterine cancer, glioma, glioblastoma, neuroblastoma, breast cancer, pancreatic ductal carcinoma, thymoma, B-CLL, leukemia, B-cell lymphoma, and cancer infiltrated with immune cells (e.g., T cells and / or NK cells) that express receptors for IGSF8 (e.g., KIR3DL1, KIR3DL2, and / or KLRC1 / D1).

[0054] In certain embodiments, the sample comprises cells, serum, peritumoral tissue, and / or intratumoral tissue obtained from the subject.

[0055] In certain embodiments, the subject is a human.

[0056] Another aspect of the present invention provides an isolated or recombinant monoclonal antibody or antigen-binding fragment thereof specific for IGSF8 (e.g., specific for the Ig-V set domain or D1 domain of the ECD of IGS8), wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising VH CDR1, VH CDR2, and VH CDR3, and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3, wherein: (a1) VH CDR1, VH CDR2, and VH CDR3 comprise, consist essentially of, or consist of the amino acid sequences of SEQ ID NOs: 714, 715, and 716, respectively; VL CDR1, VL CDR2, and VL CDR3 comprise, consist essentially of, or consist of the amino acid sequences of SEQ ID NOs: 717, 718, and 719, respectively; or (a2) VH CDR1, VH CDR2, and VH CDR3 comprise, consist essentially of, or consist of the amino acid sequences of SEQ ID NOs: 717, 718, and 719, respectively. or (b1) VH CDR1, VH CDR2 and VH CDR3 comprise, consist essentially of, or consist of the amino acid sequences of SEQ ID NOs: 720, 721 and 722, respectively; VL CDR1, VL CDR2 and VL CDR3 comprise, consist essentially of, or consist of the amino acid sequences of SEQ ID NOs: 723, 724 and 725, respectively; or (b2) VH CDR1, VH CDR2 and VH CDR3 comprise, consist essentially of, or consist of the amino acid sequences of SEQ ID NOs: 760, 761 and 762, respectively; CDR1, VL CDR2 and VL CDR3 comprise, consist essentially of, or consist of the amino acid sequences of SEQ ID NOs: 763, 764 and 765, respectively;or (c) the VH CDR1, VH CDR2 and VH CDR3 comprise, consist essentially of, or consist of the amino acid sequence of any of the VH CDR1, VH CDR2 and VH CDR3 sequences of Table D and Table G, respectively; the VL CDR1, VL CDR2 and VL CDR3 comprise, consist essentially of, or consist of the amino acid sequence of any of the VL CDR1, VL CDR2 and VL CDR3 sequences of Table D and Table G, respectively; or (d) the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 comprise the VH CDR1, VH CDR2 VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of any one of the antibodies of Table D and Table G, respectively. optionally, the antibodies and antigen-binding fragments thereof do not have the identical VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences of the L1 and L2 antibodies (e.g., the antibody is not L1 and is not L2);

[0057] In certain embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises: (1) a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences, respectively, of any one of the antibodies of Table D; or (2) a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 sequences, respectively, of any one of the antibodies of Table G.

[0058] In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a VH and a VL, wherein (a) the VH comprises a VH FR1, a VH FR2, a VH FR3, and / or a VH FR4 that comprise (i) the amino acid sequence of the corresponding VH FR sequence of any one or more antibodies in Table D (or Table G), (ii) an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the corresponding VH FR sequence of any one or more antibodies in Table D (or Table G); or (iii) an amino acid sequence with up to 1, 2, 3, 4, or 5 substitutions, deletions, and / or additions compared to the corresponding VH FR sequence of any one or more antibodies in Table D (or Table G); and / or (b) the VL comprises (i) the corresponding VL of the amino acid sequence of any one or more antibodies in Table D (or Table G). or (iii) a VL FR1, VL FR2, VL FR3, and / or VL FR4 comprising an amino acid sequence having at most 1, 2, 3, 4, or 5 substitutions, deletions, and / or additions compared to the corresponding VL FR sequence of any one or more antibodies in Table D (or Table G).

[0059] In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a VH and a VL, wherein (a1) the VH comprises the amino acid sequence of SEQ ID NOs: 734, 735, and 736, respectively; and the VL comprises the amino acid sequence of SEQ ID NOs: 737, 738, and 739, respectively; or (a2) the VH comprises the amino acid sequence of SEQ ID NOs: 774, 775, and 776, respectively; and the VL comprises the amino acid sequence of SEQ ID NOs: 777, 778, and 779, respectively; or (b1) the VH comprises the amino acid sequence of SEQ ID NOs: 774, 775, and 776, respectively; and the VL comprises the amino acid sequence of SEQ ID NOs: 777, 778, and 779, respectively; or (b2) the VH comprises the amino acid sequence of SEQ ID NOs: 780, 781 and 782, respectively; and the VL comprises the amino acid sequence of SEQ ID NOs: 783, 784 and 785, respectively; or (c) the VH comprises the amino acid sequence of any of the VH sequences in Table D and Table G; and the VL comprises the amino acid sequence of any of the VL sequences in Table D and Table G.

[0060] In some embodiments, the VH and VL sequences comprise the amino acid sequences of the VH and VL sequences of an antibody of any one of Tables D and G, respectively.

[0061] In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a human-mouse chimeric antibody, a humanized antibody, a human antibody, a CDR-grafted antibody, or a resurfaced antibody.

[0062] In some embodiments, the antigen-binding fragment thereof is a Fab, Fab', F(ab'), F d , single chain Fv or scFv, disulfide-linked F v , V-NAR domain, IgNar, intrabody, IgGΔCH2, minibody, F(ab')3, tetrabody, triabody, diabody, single domain antibody, DVD-Ig, Fcab, mAb2, (scFv)2, or scFv-Fc.

[0063] In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain constant region, wherein (a) the heavy chain constant region is wild-type human IgG1, human IgG2, human IgG3, or human IgG4; or (b) the heavy chain constant region has an Fc domain that is deficient in antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and / or antibody-dependent cellular phagocytosis (ADCP).

[0064] In some embodiments, the heavy chain constant region having a missing Fc domain is selected from the group consisting of IgG1-L234A / L235A (IgG1-LALA), IgG1-L234A / L235A / P329G (IgG1-LALA-PG), IgG1-N297A / Q / G (IgG1-NA), IgG1-L235A / G237A / E318A (IgG1-AAA), IgG1-G236R / L328R (IgG1-RR), IgG1-S298G / T299A (IgG1-GA), IgG1-L234F / L235E / P331S (IgG1- FES), IgG1-L234F / L235E / D265A (IgG1-FEA), IgG4-L234A / L235A (IgG4-LALA), IgG4-S228P / L235E (IgG4-PE), IgG1-E233P / L234V / L235A / G236del / S267K, IgG2-H268Q / V309L / A30S / P331S (IgG2m4), and IgG2-V234A / G237A / P238S / H268A / V309L / A330S / P331S (IgG2c4d).

[0065] In some embodiments, the monoclonal antibody or antigen-binding fragment thereof has a K of less than about 25 nM, less than 20 nM, less than 15 nM, less than 10 nM, less than 5 nM, less than 2 nM, or less than 1 nM. d It binds to IGSF8.

[0066] In a particular embodiment, the present invention provides a monoclonal antibody or antigen-binding fragment thereof that competes with a monoclonal antibody or antigen-binding fragment thereof of the present invention for binding to IGSF8.

[0067] Another aspect of the present invention provides a monoclonal antibody or antigen-binding fragment thereof specific to IGSF8, comprising: (1) a heavy chain variable region (HCVR) comprising an HCVR CDR1-CDR3 sequence that is at least 95% (e.g., 100%) identical to, or has up to 1, 2, 3, 4, 5, 6, 7, 8, or 9 substitutions therein, of the HCVR CDR1-CDR3, respectively, of any one of antibodies C1 to C39, e.g., C30 to C39; and (2) a light chain variable region (LCVR) comprising an LCVR CDR1-CDR3 sequence that is at least 95% (e.g., 100%) identical to, or has up to 1, 2, 3, 4, 5, 6, 7, 8, or 9 substitutions therein, of the LCVR CDR1-CDR3, respectively, of any one of antibodies C1 to C39, e.g., C30 to C39.

[0068] A related aspect of the invention provides a monoclonal antibody or antigen-binding fragment thereof that competes with a monoclonal antibody or antigen-binding fragment thereof of the invention for binding to IGSF8.

[0069] In yet another related aspect, the present invention provides a monoclonal antibody or antigen-binding portion / fragment thereof that specifically binds to the D1 ECD (or Ig-V set domain) of IGSF8 and inhibits binding to KIR3DL1 / 2, for example, binding to the D2 domain of KIR3DL1 / 2 (e.g., an epitope including S165, I171, and / or M186 of KIR3DL1 / 2).

[0070] Another aspect of the present invention provides polynucleotides encoding the monoclonal antibodies of the present invention, their heavy or light chains, or antigen-binding portions / fragments thereof.

[0071] In a related aspect, the invention provides polynucleotides that hybridize under stringent conditions to the polynucleotides of the invention or their complements.

[0072] Another aspect of the present invention provides a vector comprising a polynucleotide of the present invention.

[0073] Another aspect of the present invention provides a host cell comprising a polynucleotide of the present invention, or a vector of the present invention, for expressing the encoded monoclonal antibody of the present invention, its heavy or light chain, or antigen-binding portion / fragment thereof.

[0074] Another aspect of the present invention provides a method for producing a monoclonal antibody of the present invention, its heavy or light chain, or its antigen-binding site / fragment of the present invention, comprising the steps of: (i) culturing a host cell of the present invention capable of expressing a monoclonal antibody of the present invention, its heavy or light chain, or its antigen-binding site / fragment, under conditions suitable for expressing the monoclonal antibody, its heavy or light chain, or its antigen-binding site / fragment; and (ii) recovering / isolating / purifying the expressed monoclonal antibody of the present invention, its heavy or light chain, or its antigen-binding site / fragment.

[0075] Another aspect of the present invention provides a method for modulating an immune response in a subject in need thereof, the method comprising inhibiting the interaction of IGSF8 with a receptor for IGSF8 selected from KIR3DL1, KIR3DL2, and KLRC1 / D2 heterodimers.

[0076] Another aspect of the present invention provides a method of immunotherapy for treating cancer in a subject in need thereof, comprising inhibiting the interaction of IGSF8 with a receptor for IGSF8 selected from KIR3DL1, KIR3DL2, and KLRC1 / D2 heterodimers.

[0077] Another aspect of the present invention provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an IGSF8 (Immunoglobulin superfamily 8) modulator (e.g., antagonist).

[0078] Another aspect of the present invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a KIR3DL1 antagonist that inhibits interaction with IGSF8.

[0079] Another aspect of the present invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a KIR3DL2 antagonist that inhibits its interaction with IGSF8.

[0080] Another aspect of the present invention provides a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a KLRC1 / D1 antagonist that inhibits interaction with IGSF8.

[0081] Another aspect of the present invention provides the use of an IGSF8 antagonist, a KIR3DL1 antagonist, a KIR3DL2 antagonist, or a KLRC1 / D1 antagonist that inhibits the binding of IGSF8 to its receptor selected from KIR3DL1, KIR3DL2, and a KLRC1 / D2 heterodimer, for treating cancer in a subject.

[0082] Another aspect of the present invention provides a composition comprising an IGSF8 antagonist, a KIR3DL1 antagonist, a KIR3DL2 antagonist, or a KLRC1 / D1 antagonist that inhibits the binding of IGSF8 to its receptor selected from KIR3DL1, KIR3DL2, and the KLRC1 / D2 heterodimer, for use in any of the above method claims.

[0083] Another aspect of the invention provides an antibody that specifically binds IGSF8 for use in a method of treating cancer, preferably by stimulating the activation of T cells and / or NK cells.

[0084] Another aspect of the invention provides an antibody that specifically binds IGSF8 for use in a method of treating cancer, preferably in combination with a second therapeutic agent as described herein, such as a checkpoint inhibitor-mediated immunotherapy.

[0085] Another aspect of the present invention provides a device or kit comprising at least one antibody, monoclonal antibody, heavy chain or light chain thereof, or antigen-binding portion / fragment thereof of the present invention, and optionally a label for detecting at least one of said antibody, monoclonal antibody, heavy chain or light chain, or antigen-binding portion / fragment thereof, or a complex comprising at least one of said antibody, monoclonal antibody, heavy chain or light chain, or antigen-binding portion / fragment thereof.

[0086] Another aspect of the present invention provides a fusion protein comprising an IGSF8 polypeptide and an Fc region of an antibody.

[0087] Another aspect of the present invention provides polynucleotides encoding the fusion proteins of the present invention.

[0088] Another aspect of the present invention provides a vector comprising a polynucleotide encoding the fusion protein of the present invention.

[0089] Another aspect of the present invention provides a host cell comprising a polynucleotide encoding a fusion protein of the present invention, or a vector comprising a polynucleotide encoding a fusion protein of the present invention, for expressing the encoded fusion protein.

[0090] Another aspect of the present invention provides a method for producing a fusion protein of the present invention, comprising the steps of: (i) culturing a host cell of the present invention capable of expressing the fusion protein under conditions suitable for expressing the fusion protein; and (ii) recovering / isolating / purifying the expressed fusion protein.

[0091] Another aspect of the present invention provides a method for suppressing the activity of primary NK cells or T cells, the method comprising the step of contacting said primary NK cells or said T cells with a fusion protein of the present invention.

[0092] Another aspect of the present invention provides a method for detecting the presence or level of IGSF8 polypeptide in a sample, comprising the step of contacting the IGSF8 polypeptide in the sample with an antibody, monoclonal antibody, or antigen-binding portion / fragment thereof of the present invention, wherein the antibody, monoclonal antibody, or antigen-binding portion / fragment thereof may be labeled with or attached to a detectable label.

[0093] Another aspect of the present invention provides a method for monitoring the progression of a disorder associated with abnormal (e.g., higher than normal) IGSF8 expression in a subject, comprising: a) detecting a first level of IGSF8 in a sample obtained from the subject at a first time point using an antibody, monoclonal antibody, or antigen-binding site / fragment thereof of the present invention; b) repeating step a) at a subsequent time point to obtain a second level of IGSF8; and c) comparing the first and second levels of IGSF8 detected in steps a) and b), respectively, to monitor the progression of the disorder in the subject, wherein a second level higher than the first level indicates that the disease has progressed.

[0094] Another aspect of the present invention provides a method for predicting the clinical outcome of a subject suffering from a disorder associated with aberrant (e.g., higher than normal) IGSF8 expression, comprising the steps of: a) determining the level of IGSF8 in a first sample obtained from the subject using an antibody, monoclonal antibody, or antigen-binding portion / fragment thereof of the present invention; b) determining the level of IGSF8 in a second sample obtained from a control subject with a good clinical outcome using an antibody, monoclonal antibody, or antigen-binding portion / fragment thereof of the present invention; and c) comparing the levels of IGSF8 in the first and second samples; wherein a significantly higher level of IGSF8 in the first sample compared to the level of IGSF8 in the second sample (e.g., a >20%, >50% or greater increase) is indicative of the subject having a poorer clinical outcome, and / or a significantly lower level of IGSF8 in the first sample compared to the level of IGSF8 in the second sample (e.g., a >20%, >50% or greater decrease) is indicative of the subject having a better clinical outcome.

[0095] Another aspect of the present invention provides a method for assessing the effectiveness of a therapy for a disorder associated with abnormal (e.g., higher than normal) IGSF8 expression in a subject, comprising: a) determining the level of IGSF8 using an antibody, monoclonal antibody, or antigen-binding site / fragment thereof in a first sample obtained from the subject before providing at least a portion of the therapy to the subject; and b) repeating step a) in a second sample obtained from the subject following the provision of said portion of the therapy, wherein a significantly lower level of IGSF8 in the second sample compared to the first sample (a decrease of >20%, >50% or more) is an indication that the therapy is effective in inhibiting the disorder in the subject; and / or a substantially identical or higher level of IGSF8 in the second sample compared to the first sample is an indication that the therapy is not effective in inhibiting the disorder in the subject.

[0096] Another aspect of the present invention provides a method for assessing the effectiveness of a test compound for inhibiting a disorder associated with abnormal (e.g., higher than normal) IGSF8 expression in a subject, comprising the steps of: a) determining the level of IGSF8 in a first sample obtained from the subject using an antibody, monoclonal antibody, or antigen-binding portion / fragment thereof of the present invention, wherein the first sample has been exposed to an amount of the test compound; and b) determining the level of IGSF8 in a second sample obtained from the subject using an antibody, monoclonal antibody, or antigen-binding portion / fragment thereof of the present invention, wherein the second sample has not been exposed to the test compound; wherein a significantly lower level of IGSF8 in the first sample compared to the level in the second sample (a decrease of >20%, >50% or more) is an indication that the amount of the test compound is effective for inhibiting the disorder in the subject, and / or a substantially identical level of IGSF8 in the first sample compared to the level in the second sample is an indication that the amount of the test compound is not effective for inhibiting the disorder in the subject.

[0097] Another aspect of the present invention provides a screening method for functional IGSF8 antagonists, comprising contacting a candidate agent (e.g., a small molecule, peptide, aptamer, polynucleotide, etc.) with a co-culture of NK cells and target cells that express IGSF8 and are resistant to NK cell-mediated cytotoxicity, and identifying a candidate agent that promotes NK cell-mediated cytolytic activity against the target cells, thereby identifying the candidate agent as an IGSF8 antagonist.

[0098] Another aspect of the present invention provides a method for screening for a functional IGSF8 antagonist, comprising contacting a candidate agent (e.g., a small molecule, peptide, aptamer, polynucleotide, etc.) with Jurkat NFAT reporter cells in the presence of a T cell activation signal and IGSF8; if the reporter cells are not activated in the absence of the candidate agent but are activated in the presence of the candidate agent, the candidate agent is identified as a functional IGSF8 antagonist.

[0099] Another aspect of the present invention provides an antibody that specifically binds to KIR3DL1 / 2 for use in a method of treating cancer by inhibiting KIR3DL1 / 2-IGSF8 interaction, thereby stimulating NK cell activation.

[0100] Another aspect of the present invention provides an antibody that specifically binds KIR3DL1 / 2 for use in a method of treating cancer, preferably in combination with a second therapeutic agent of the invention described herein, such as a checkpoint inhibitor-mediated immunotherapy agent.

[0101] Another aspect of the present invention provides a monoclonal antibody or antigen-binding fragment thereof specific to KIR3DL1 / 2, preferably specific to the second / middle / D2 Ig-like domain of the ECD of KIR3DL1 / 2, or an epitope comprising residues S165, I171, and / or M186.

[0102] Another aspect of the present invention provides a monoclonal antibody or antigen-binding fragment thereof that competes with the monoclonal antibody or antigen-binding fragment thereof for binding to KIR3DL1 / 2.

[0103] Another aspect of the present invention provides a monoclonal antibody or antigen-binding portion / fragment thereof that specifically binds to the middle / D2 ECD of KIR3DL1 / 2 (e.g., specifically binds to an epitope comprising residues S165, I171, and / or M186), and inhibits binding of IGSF8 to KIR3DL1 / 2.

[0104] It is to be understood that any one embodiment of the present invention, including embodiments described only in the examples or claims, can be freely combined with any other one or more additional embodiments of the present invention, unless expressly and clearly excluded or inappropriate. [Brief explanation of the drawings]

[0105] [Figure 1] We present the results of a genome-wide co-culture screen of natural killer (NK) cells and a cancer cell line (colon cancer cell line Colo205) and show that loss of IGSF8 function in Colo205 enhances NK cell cytotoxicity against Colo205. The IGSF8 gene was the top two hit whose loss sensitized Colo205 cell killing by NK cells. [Figure 2A] Figure 2A shows the dose-response curves of primary NK cells from human donor 2 and human donor 3 treated with human Fc control or human IGSF8-hFc (human Fc-tagged IGSF8). Compared to the Fc control, NK cell viability significantly decreases with increasing concentrations of IGSF8-hFc. [Figure 2B] Figure 2B shows the dose-response curves of primary T cells from human donor 2 treated with human Fc (hFc) control or human IGSF8-hFc (human Fc-tagged IGSF8). Compared to the hFc control, T cell viability is significantly reduced with increasing concentrations of IGSF8-hFc. [Figure 2C] A statistically significant (p<0.005) decrease in NK cell viability by IGSF8-Fc fusion protein in a dose-dependent manner is confirmed. [Figure 2D] The top 5 enriched KEGG pathways downregulated in RNA-seq of NK cells treated with IGSF8-hFc fusion protein or hFc control protein are shown. [Figure 2E] Relative mRNA expression of genes in NK cells treated with IGSF8-hFc fusion protein or hFc control protein is shown. [Figure 2F] 1 shows the effect of IGSF8-hFc fusion protein on primary NK cell proliferation. [Figure 2G] 1 shows the effect of IGSF8-hFc fusion protein on primary CD4+ T cell proliferation. [Figure 2H] 1 shows the effect of IGSF8-hFc fusion protein on primary CD4+ T cell activation. [Figure 3A] Figure 3A shows that CRISPR / Cas9-mediated deletion of IGSF8 in B16-F10 melanoma cells significantly reduces the ability of these tumor cells to grow in vivo (as measured by tumor volume in mm3) in a mouse xenograph model (n = 8 mice per group). sgIGSF8-1 and -2 represent two experimental groups in which the IGSF8 gene was deleted in B16-F10 tumor cells using two different CRISPR / Cas9 sgRNAs targeting different regions of IGSF8 before injecting these IGSF8-deleted B16-F10 tumors into mice. As a control, the AAV integration site AAVS1 was similarly deleted in control B16-F10 tumor cells using an sgRNA specific for AAVS1. [Figure 3B] Figure 3B shows that the delayed in vivo tumor growth after IGSF8 deletion is not due to differences in the relative in vitro cell growth rates of gene-deleted B16-F10 melanoma cells: there is no statistically significant difference in the in vitro cell proliferation rate between IGSF8-deleted B16-F10 cells and AAVS1-deleted B16-F10 cells. [Figure 4]We show that deletion of IGSF8 by CRISPR / Cas9-mediated gene editing in various cancer cell lines promotes CXCL10 expression, measured as the relative fold increase in CXCL10 expression compared to the same cancer cells in which AAVS1 was deleted. H292 (NCI-H292) is a human mucoepidermoid lung carcinoma cell line, A549 is a human lung carcinoma cell line, Colo205 is a Dukes type D colon adenocarcinoma cell line, N87 is a human gastric carcinoma cell line, and A375 is a human melanoma cell line. [Figure 5A] Figures 5A and 5C show the enhanced relative expression of various genes in B16-F10 cells (Figures 5A and 5C) and tumors (Figures 5B and 5D) upon deletion of AAVS1 or IGSF8 by CRISPR / Cas9-mediated gene editing. *: P<0.05; **: P<0.01; ***: P<0.001. [Figure 5B] Figures 5A and 5C show the enhanced relative expression of various genes in B16-F10 cells (Figures 5A and 5C) and tumors (Figures 5B and 5D) upon deletion of AAVS1 or IGSF8 by CRISPR / Cas9-mediated gene editing. *: P<0.05; **: P<0.01; ***: P<0.001. [Figure 5C] Figures 5A and 5C show the enhanced relative expression of various genes in B16-F10 cells (Figures 5A and 5C) and tumors (Figures 5B and 5D) upon deletion of AAVS1 or IGSF8 by CRISPR / Cas9-mediated gene editing. *: P<0.05; **: P<0.01; ***: P<0.001. [Figure 5D] Figures 5A and 5C show the enhanced relative expression of various genes in B16-F10 cells (Figures 5A and 5C) and tumors (Figures 5B and 5D) upon deletion of AAVS1 or IGSF8 by CRISPR / Cas9-mediated gene editing. *: P<0.05; **: P<0.01; ***: P<0.001. [Figure 6A] Gene expression of IGSF8 in human cancer cell lines is shown (date retrieved from the Broad Institute Cancer Cell Line Encyclopedia (CCLE)). [Figure 6B]Figure 1 shows statistically significant elevated expression of IGSF8 in various tumors in The Cancer Genome Atlas (TCGA) cohort. [Figure 6C] Clinical relevance of IGSF8 in The Cancer Genome Atlas (TCGA) cohort. Higher IGSF8 expression is associated with worse clinical outcomes in different cancer types. [Figure 7] 1 shows the binding affinity of representative recombinant anti-IGSF8 antibodies of the present invention to the IGSF8 extracellular domain and their EC50 values ​​measured by ELISA. [Figure 8] 1 shows an antibody-dependent cellular cytotoxicity (ADCC) assay and associated EC50 values ​​of representative anti-IGSF8 antibodies of the present invention using NK cells as effector cells and A431 cancer cells as target cells. [Figure 9] 1 shows a human CXCL10 ELISA assay of Colo205 cells treated with a representative anti-IGSF8 antibody of the invention (10 μg / mL). [Figure 10]

[0039] Figure 1 shows the effect of a representative anti-IGSF8 monoclonal antibody of the present invention on tumor growth in B16 syngeneic mice. B16-F10 cells were subcutaneously injected into wild-type (WT) C57BL / 6 mice. Mice were then treated with 2 mg / kg of anti-IGSF8 antibody or control human IgG1 every 3 days, starting on day 6, for a total of 4 doses. Data are shown as mean ± SEM (n = 8 mice per group). [Figure 11] 1 is a line graph showing that there is no significant difference in body weight between groups of experimental mice treated with anti-IGSF8 antibody or control human IgG1. [Figure 12] 1 shows synergy between the subject anti-IGSF8 and anti-PD-1 antibodies in reducing B16-F10 melanoma tumor volume growth in syngeneic mice. [Figure 13A] 1 shows the effect of IGSF8-hFc fusion protein on the cytolytic activity of NK cells co-cultured with K562 cells. [Figure 13B]1 shows the effect of IGSF8-hFc fusion protein on perforin production by NK cells in an NK-K562 co-culture model. [Figure 14] Figure 1 shows the effect on the cytolytic activity of NK cells co-cultured with K562 cells, K562 cells overexpressing IGSF8, or IGSF8 knockout K562 cells. NK cells were derived from two different donors. [Figure 15A] The topological domains of IGSF8 are shown. [Figure 15B] 1 shows the effect of the D1 and D2-4 domains of the IGSF8 protein on the cytolytic activity of NK cells co-cultured with K562 cells. [Figure 16A] We outline a CRISPR screening strategy to deorphanize the receptor for IGSF8 on NK cells. [Figure 16B] A dot plot of the top selected genes from the CRISPR screen is shown. [Figure 17A] 1 shows the core map of the lentiviral vector used to express KIR receptors. [Figure 17B] Binding of biotin-labeled IGSF8 to different KIR family proteins is shown. [Figure 17C] 1 shows the core maps of the two lentiviral vectors used to express the KLRC1 / D1 heterodimeric receptor. [Figure 17D] This shows that only the KLRC1 / D1 heterodimer, but not each monomer alone, binds to recombinant IGSF8-hFc protein. [Figure 17E] We show that the binding of IGSF8 to KIR3D1 / 2 or KLRC1 / D1 receptors is mediated by the D1 (Ig-V set) ECD of IGSF8. [Figure 18A] The topological domains of KIR3DL1 / 2 are shown, as well as the individual domain constructs used to narrow down the binding domain of KIR3DL1 / 2 to IGSF8. [Figure 18B]Binding of biotin-labeled IGSF8 to different domains of KIR3DL1 / 2 is shown. [Figure 19A] Figure 19A shows a multiple sequence alignment of KIR family proteins and the three residues required for IGSF8 binding. SEQ ID NOS: 822-825 are listed in order of appearance. [Figure 19B] The crystal structure of KIR3DL1 and the three residues required for IGSF8 binding are shown. [Figure 20] Binding of biotin-labeled IGSF8 to different mutants of KIR3DL1 / 2 is shown. [Figure 21] Figure 1 shows the binding and EC50 values ​​of IGSF8 monoclonal antibodies (mAbs) B34, 1B4, 2B4, 1C2, 3F12, B46, and B104 to CT26 cells expressing human IGSF8 on their cell surface. At least some of these antibodies (e.g., 1B4, B46, and B104) also bind to mouse IGSF8 expressed on CT26 cells (data not shown). [Figure 22] Binding of IGSF8 mAb to the D1 domain of IGSF8 on CT26 cells is shown. [Figure 23A] Figure 1 shows two embodiments of antibody blocking assays. In the left panel, CT26 cells expressing the ligand IGSF8 are treated with soluble biotin-labeled receptor (KIR3DL1 / 2) and anti-IGSF8 mAb, after which bound receptor is detected with PE-streptavidin. In the right panel, MC38 cells expressing the IGSF8 ligand are contacted with KLR- or KIR-receptor-expressing CT26 cells, and anti-IGSF8 antibodies capable of blocking MC38-CT26 cell / cell conjugates reduce the formation of FACS-detectable conjugates. [Figure 23B] 1 shows the blocking of cell-cell conjugate formation between IGSF8-expressing MC38 cells and KIR3DL2-expressing CT26 cells by selected anti-IGSF8 antibodies. [Figure 23C]1 shows the blocking of cell-cell conjugate formation between IGSF8-expressing MC38 cells and KLRC1 / D1 heterodimer-expressing CT26 cells by anti-IGSF8 antibodies. [Figure 24A] FIG. 24A is a diagram of the NK cell suppression assay of FIG. 24B. [Figure 24B] FIG. 24B shows that IGSF8-mediated inhibition of K562 cell killing by human primary NK cells can be reversed by anti-IGSF8 mAb. [Figure 25] Figure 25A shows in vivo anti-tumor efficacy using the B16-F10 syngeneic model, and Figure 25B shows the response of individual mice treated with anti-IGSF8 mAb or an isotype-matched IgG control. [Figure 26] Figure 26A shows in vivo anti-tumor efficacy using the LLC syngeneic mouse model. Figure 26B shows in vivo anti-tumor efficacy using the CT26 syngeneic mouse model. [Figure 27] Relative mRNA expression of genes in LLC syngeneic mouse model is shown. [Figure 28] Figure 28 shows the amino acid sequences of the heavy and light chain variable regions of the L1 and L2 antibodies. The CDR sequences according to the IMGT numbering scheme are in boxes. The underlined sequences include the CDR regions as well as adjacent framework region sequences that may affect binding affinity. Figure 28 discloses SEQ ID NOs: 669, 809, 703, and 819, respectively, in the order they appear. [Figure 29] Figure 1 shows a heatmap of negative selection of mutants within the L1 heavy chain CDR. Gray boxes represent amino acid substitutions that reduce binding compared to the original sequence of the L1 CDR residue at the same position. The darker the shade of gray, the weaker the binding compared to the original residue. [Figure 30] Heatmap of positive selection of mutants within the L1 heavy chain CDR. Gray boxes represent amino acid substitutions that enhance / increase binding compared to the original sequence of the L1 CDR residue at the same position. The darker the shade of gray, the stronger the binding compared to the original residue. [Figure 31]1 shows a heatmap of negative selection of mutants within the L1 light chain CDRs. [Figure 32] 1 shows a heatmap of positive selection of variants within the L1 light chain CDR. [Figure 33] 1 shows a heatmap of negative selection of mutants within the L2 heavy chain CDRs. [Figure 34] 1 shows a heatmap of the positive selection of mutants within the L2 heavy chain CDRs. [Figure 35] 1 shows a heatmap of negative selection of mutants within the L2 light chain CDR. [Figure 36] A heatmap of the positive selection of variants within the L2 light chain CDR is shown. [Figure 37-1] Figures 37A-37D show the binding affinities of representative L1 and L2 antibodies of the present invention to human (Figure 37A), monkey (Figure 37B), and mouse (Figure 37C) IGSF8 expressed on the surface of CT26 cells, as well as their EC50 values ​​measured by FACS (Figure 37D). [Figure 37-2] Figures 37A-37D show the binding affinities of representative L1 and L2 antibodies of the present invention to human (Figure 37A), monkey (Figure 37B), and mouse (Figure 37C) IGSF8 expressed on the surface of CT26 cells, as well as their EC50 values ​​measured by FACS (Figure 37D). [Figure 38] Figure 38A shows lentivirus-mediated CRISPR / Cas9 knockdown of KIR3DL2 in NK cells as measured by FACS. Figure 38B shows that IGSF8-mediated suppression of K562 cell killing by human primary NK cells can be reversed by loss of KIR3DL2 on NK cells. [Figure 39] We show by FACS that representative L1 and L2 antibodies can completely block the interaction between IGSF8 and KIR3DL2 in a dose-dependent manner. [Figure 40A]Figures 40A-40D show the in vitro anti-tumor cell efficacy of representative L1 and L2 antibodies using co-culture models of primary NK cells and cancer cell lines Jurkat (Figure 40A), SU-DHL2 (Figure 40B), LNCap (Figure 40C), and K562 (Figure 40D). ****: P<0.0001. [Figure 40B] Figures 40A-40D show the in vitro anti-tumor cell efficacy of representative L1 and L2 antibodies using co-culture models of primary NK cells and cancer cell lines Jurkat (Figure 40A), SU-DHL2 (Figure 40B), LNCap (Figure 40C), and K562 (Figure 40D). ****: P<0.0001. [Figure 40C] Figures 40A-40D show the in vitro anti-tumor cell efficacy of representative L1 and L2 antibodies using co-culture models of primary NK cells and cancer cell lines Jurkat (Figure 40A), SU-DHL2 (Figure 40B), LNCap (Figure 40C), and K562 (Figure 40D). ****: P<0.0001. [Figure 40D] Figures 40A-40D show the in vitro anti-tumor cell efficacy of representative L1 and L2 antibodies using co-culture models of primary NK cells and cancer cell lines Jurkat (Figure 40A), SU-DHL2 (Figure 40B), LNCap (Figure 40C), and K562 (Figure 40D). ****: P<0.0001. [Figure 41] Figures 41A-41B show the in vitro anti-tumor cell efficacy of representative L1 and L2 antibodies using a co-culture model of PBMCs with cancer cell lines H1437 (Figure 41A) and SKBR3 (Figure 41B). ****: P<0.0001. [Figure 42] Figures 42A-42B show the in vitro antitumor cell efficacy of representative L1 and L2 antibodies using a co-culture model of PBMCs with cancer cell lines SW480 (Figure 42A) and H520 (Figure 42B). The efficacy of L1 or L2 antibodies bearing normal human IgG1 or a deletion mutant of IgG1 (IgG1-LALA) was compared. **: P<0.01; ***: P<0.001; ****: P<0.0001. [Figure 43A]Figure 43A shows the in vivo anti-tumor efficacy of a representative L1 antibody using the B16-F10 syngeneic model. [Figure 43B] Figure 43B shows a comparison between L1 antibodies with normal human IgG1, IgG4, and a deletion mutant of IgG1 (IgG1-LALA). **: P<0.01; ***: P<0.001; ****: P<0.0001. [Figure 44] Expression of marker genes for effector NK and T cells in B16 tumors treated with human normal IgG1, IgG4, and the L1 antibody containing a deletion mutant of IgG1 (IgG1-LALA) is shown. *: P<0.05 **: P<0.01. DETAILED DESCRIPTION OF THE INVENTION

[0106] 1. Overview The immunoglobulin superfamily member 8 (IGSF8) gene encodes a member of the immunoglobulin protein superfamily with a single transmembrane (TM) domain. IGSF8 contains an extracellular Ig V-set domain, which is found in diverse protein families, including T cell receptors such as CD2, CD4, CD80, and CD86, and immune checkpoints such as PD1, LAG3, and PDL1. In humans, IGSF8 appears to be overexpressed in histological tissues of selected cancer patients compared to control levels in normal human tissues.

[0107] The invention described herein is based in part on the discovery that IGSF8 is a novel cancer therapeutic target and, therefore, that IGSF8 antagonists can be used to treat such cancers. The data presented herein demonstrate that IGSF8 is specifically expressed in cancer cells and is highly expressed in multiple types of cancer, particularly melanoma, cervical cancer, non-small cell lung cancer, colorectal cancer, and many other cancers. IGSF8 interacts with T cells and NK (natural killer) cells, inhibiting their proliferation and / or reducing their survival. Meanwhile, knocking out the IGSF8 gene or alternatively inactivating IGSF8 function improves tumor infiltration by T cells and NK cells and enhances their cytolytic activity in vivo.

[0108] More specifically, the present invention is based in part on the discovery that IGSF8 has a previously unrecognized function as a novel inhibitory ligand for activated NK cells, functioning as an immune checkpoint that controls NK cell-mediated cancer immunosurveillance. IGSF8 recombinant protein suppresses the proliferation and cytolytic activity of activated primary NK cells or T cells. Meanwhile, IGSF8 inhibition (e.g., with anti-IGSF8 monoclonal antibodies) results in in vivo efficacy in multiple rodent oncological animal models.

[0109] The invention described herein, which is based in part on IGSF8-mediated inhibition of NK cell function, has advantages over MHC class I (HLA)-based NK cell inhibition, in part because, while MHC I molecules are highly variable between unrelated individuals, IGSF8 is not only non-polymorphic between different individuals but is also highly conserved across species (e.g., between humans and laboratory animals such as mice), allowing anti-IGSF8 agents, including anti-human IGSF8 monoclonal antibodies, to be tested directly in animal (e.g., mouse) models.

[0110] The invention described herein is further based on the finding that IGSF8 can specifically bind to primary NK cells via its D1 domain-Ig V set domain, since truncated IGSF8 having only the D1 domain as its extracellular domain is sufficient to suppress NK cells, whereas other truncated IGSF8 proteins lacking only the D1 domain completely lose the NK cell suppressive function.

[0111] Furthermore, the invention described herein is based on the discovery that IGSF8 binds to NK cells by specifically binding to the KIR family receptor KIR3DL2 (and to a lesser extent KIR3DL1) expressed on the surface of NK cells. Just as tumors can evade T cell-mediated immunity by downregulating MHC-I or inhibiting T cell function by expressing PD-L1 ligands and binding to PD1 on T cells, tumors may similarly upregulate IGSF8 to evade NK cell-mediated immune surveillance of cancer by binding to specific KIR receptors for IGSF8 (e.g., KIR3DL1 / 2) on NK cells.

[0112] The invention described herein is further based on the discovery that IGSF8 binds to NK cells by specifically binding to the KLRC1 / KLRD1 heterodimeric receptor (but not KLRC1 or KLRD1 monomers alone) expressed on the surface of NK cells. As described above, tumors can upregulate IGSF8 to evade NK cell-mediated cancer immune surveillance by binding to the IGSF8-specific KLRC1 / D1 heterodimeric receptor on NK cells.

[0113] Because IGSF8 is known to be expressed at high levels in multiple tumor types, immunotherapy using anti-IGSF8 mAb as a checkpoint inhibitor could expand the pool of patients who respond to checkpoint inhibitor treatment. Furthermore, patients with tumors that have acquired resistance to PD-1 therapy may also express IGSF8 as an alternative immune evasion strategy, and IGSF8 blockade may provide an additional avenue for overcoming resistance to PD-1 immunotherapy.

[0114] The invention described herein is further based on the discovery that anti-IGSF8 therapy acts synergistically with anti-PD1 / PD-L1 therapy, in part by activating both T cells and NK cells in the tumor microenvironment, as demonstrated by the animal models herein.

[0115] Thus, the present invention provides monoclonal antibodies and antigen-binding fragments thereof that specifically bind to IGSF8 (particularly its Ig V-set extracellular domain). Such antibodies may inhibit one or more functions of IGSF8, such as the binding of IGSF8 to NK cell surface receptors (e.g., KIR3DL1 or KIR3DL2 or KLRC1 / D1), thereby reversing or reducing IGSF8-mediated inhibition of NK cell activity and / or viability. The present invention further provides nucleic acids encoding anti-IGSF8 antibodies or antigen-binding fragments thereof, vectors carrying such nucleic acid coding sequences for expression in suitable host cells, and methods for producing such antibodies or antigen-binding fragments thereof by culturing host cells capable of expressing such antibodies or antigen-binding fragments thereof. The present invention further provides methods of using such antibodies for diagnostic, prognostic, and therapeutic purposes.

[0116] Several antibodies against IGSF8 have been generated, many of which have been validated for binding and blocking IGSF8, and have shown enhanced ADCC and NK and / or T cell-mediated cancer cell killing against IGSF8-expressing cancer cells. More importantly, the data presented herein demonstrate that simultaneous inhibition of IGSF8 function and the PD-1 / PD-L1 immune checkpoints results in synergistic effects in an in vivo mouse model of cancer (melanoma).

[0117] The antibodies described herein are characterized in part by their high binding affinity to IGSF8. The antibodies described herein are further based in part on the surprising discovery that certain antibody formats with reduced effector function exhibit superior anti-tumor efficacy than antibodies with intact effector function.

[0118] The present invention also provides monoclonal antibodies and antigen-binding fragments thereof that specifically bind to one of the IGSF8 receptors, e.g., KIR3DL1, KIR3DL2, or KLRC1 / D1, on NK cells and / or T cells and reverse or reduce the inhibition of NK / T cell activity and / or viability due to IGSF8 binding to one or more of these receptors. Antibodies specific for KIR3DL2 or KIR3DL1 may be specific for the D2 extracellular domain of KIR3DL1 / 2, which is responsible for IGSF8 binding, and include antibodies that specifically block IGSF8 binding to residues S165, I171, and / or M186 of KIR3DL1 / 2. Such antibodies may inhibit one or more functions of KIR3DL1 / 2 and / or KLRC1 / D1, such as IGSF8 binding, and reverse or reduce IGSF8-mediated inhibition of NK cell activity and / or viability. The invention further provides nucleic acids encoding such antibodies or antigen-binding fragments thereof against KIR3DL1 or KIR3DL2 or KLRC1 / D1, vectors carrying such nucleic acid coding sequences for expression in suitable host cells, and methods for producing such antibodies or antigen-binding fragments by culturing host cells capable of expressing such antibodies or antigen-binding fragments. The invention further provides methods of using such antibodies for diagnostic, prognostic, and therapeutic purposes.

[0119] Thus, the invention described herein specifically provides methods and reagents for modulating the immune response or treating cancer by modulating (e.g., inhibiting) IGSF8 activity / antagonizing IGSF8 function, disrupting / antagonizing its interaction with one or more of its receptors on NK / T cells (e.g., KIR3DL1 or KIR3DL2 or KLRC1 / D1), in any combination with any second therapeutic agent that targets the PD-1 / PD-L1 immune checkpoint.

[0120] Detailed aspects of the present invention are further described individually in various sections below, however, it should be understood that any one embodiment of the present invention, including embodiments described only in the examples or drawings and embodiments described only under one section below, can be combined with any other embodiment(s) of the present invention.

[0121] 2.Definition The term "antibody" in its broadest sense encompasses various antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, and multispecific antibodies (e.g., bispecific antibodies). The term "antibody" also broadly refers to a molecule that comprises heavy chain complementarity-determining regions (CDRs) 1, 2, and 3 and light chain CDRs 1, 2, and 3 and is capable of binding to an antigen. The term "antibody" also includes, but is not limited to, chimeric antibodies, humanized antibodies, human antibodies, and antibodies of various species, such as mice, humans, and cynomolgus monkeys.

[0122] However, in a narrower sense, "antibody" refers to various monoclonal antibodies, including chimeric, humanized, and human monoclonal antibodies.

[0123] In some embodiments, an antibody comprises a heavy chain variable region (HCVR or VH) and a light chain variable region (LCVR or VL). In some embodiments, an antibody comprises at least one heavy chain (HC) comprising a heavy chain variable region and at least a portion of a heavy chain constant region, and at least one light chain (LC) comprising a light chain variable region and at least a portion of a light chain constant region. In some embodiments, an antibody comprises two heavy chains, each heavy chain comprising a heavy chain variable region and at least a portion of a heavy chain constant region, and two light chains, each light chain comprising a light chain variable region and at least a portion of a light chain constant region.

[0124] As used herein, a single-chain Fv (scFv), or any other antibody comprising, for example, a single polypeptide chain comprising all six CDRs (three heavy chain CDRs and three light chain CDRs), is considered to have a heavy chain and a light chain. In some such embodiments, the heavy chain is the region of the antibody that comprises the three heavy chain CDRs, and the light chain is the region of the antibody that comprises the three light chain CDRs.

[0125] As used herein, the term "heavy chain variable region (HCVR or VH)" refers to at least heavy chain CDR1 (CDR-H1 or VH-CDR1), framework 2 (HFR2 or VH-FR2), CDR2 (CDR-H2 or VH-CDR2), FR3 (HFR3 or VH-FR3), and CDR3 (CDR-H3 or VH-CDR3). In some embodiments, the heavy chain variable region also includes at least a portion of FR1 (HFR1 or VH-FR1) that is N-terminal to CDR-H1 and / or at least a portion of FR4 (HFR4 or VH-FR4) that is C-terminal to CDR-H3.

[0126] As used herein, the term "heavy chain constant region" refers to a region comprising at least three heavy chain constant domains, CH1, CH2, and CH3. Non-limiting exemplary heavy chain constant regions include gamma, delta, and alpha. Non-limiting exemplary heavy chain constant regions also include epsilon and mu. Each heavy constant region corresponds to the antibody's isotype. For example, an antibody comprising a gamma constant region is an IgG antibody (e.g., IgG1, IgG2, IgG3, IgG4), an antibody comprising a delta constant region is an IgD antibody, an antibody comprising an alpha constant region is an IgA antibody, an antibody comprising an epsilon constant region is an IgE antibody, and an antibody comprising a mu constant region is an IgM antibody.

[0127] Particular isotypes may be further subdivided into subclasses. For example, IgG antibodies include, but are not limited to, IgG1 (containing a gamma 1 constant region), IgG2 (containing a gamma 2 constant region), IgG3 (containing a gamma 3 constant region), and IgG4 (containing a gamma 4 constant region) antibodies; IgA antibodies include, but are not limited to, IgA1 (containing an alpha 1 constant region) and IgA2 (containing an alpha 2 constant region) antibodies; and IgM antibodies include, but are not limited to, IgM1 (containing a mu 1 constant region) and IgM2 (containing a mu 2 constant region) antibodies.

[0128] The heavy chain constant region contains a fragment crystallizable (Fc) domain at the C-terminus of the molecule. The primary function of the Fc region is to induce immune effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP), through interactions with cell surface receptors called Fc receptors (FcRs) and several proteins of the complement system (e.g., C1q). Different antibody isotypes may contribute to immune effector functions to different degrees, and Fc engineering strategies have been employed to enhance or reduce immune effector functions.

[0129] As used herein, the term "heavy chain" refers to a polypeptide comprising at least a heavy chain variable region, with or without a leader sequence. In some embodiments, a heavy chain comprises at least a portion of a heavy chain constant region. As used herein, the term "full-length heavy chain" refers to a polypeptide comprising a heavy chain variable region and a heavy chain constant region, with or without a leader sequence, and with or without a C-terminal lysine.

[0130] As used herein, the term "light chain variable region (LCVR or VL)" refers to the region comprising light chain CDR1 (CDR-L1 or VL-CDR1), framework (FR) 2 (LFR2 or VL-FR2), CDR2 (CDR-L2 or VL-CDR2), FR3 (LFR3 or VL-FR3), and CDR3 (CDR-L3 or VL-CDR3). In some embodiments, the light chain variable region also comprises at least a portion of FR1 (LFR1 or VL-FR1) and / or at least a portion of FR4 (LFR4 or VL-FR4).

[0131] As used herein, the term "light chain constant region" refers to a light chain constant domain C L Non-limiting exemplary light chain constant regions include lambda and kappa.

[0132] As used herein, a "light chain" refers to a polypeptide comprising at least a light chain variable region, with or without a leader sequence. In some embodiments, a light chain comprises at least a portion of a light chain constant region. As used herein, the term "full-length light chain" refers to a polypeptide comprising a light chain variable region and a light chain constant region, with or without a leader sequence.

[0133] The term "antibody fragment" or "antigen-binding fragment" (of an antibody) includes, but is not limited to, fragments capable of antigen binding, such as Fv, single-chain Fv (scFv), Fab, Fab', and (Fab')2.

[0134] An "antibody that binds to the same epitope" as a reference antibody can be determined by an antibody competition assay. This refers to an antibody that blocks the binding of the reference antibody to its antigen by 50% or more in a competition assay; conversely, the reference antibody blocks the binding of the antibody to its antigen by 50% or more in a competition assay. The term "competition," when used in the context of antibodies competing for the same epitope, means that competition between the antibodies is determined by an assay in which the antibody being tested prevents or inhibits the specific binding of the reference antibody to a common antigen.

[0135] There are many types of competitive binding assays, such as solid-phase direct or indirect radioimmunoassays (RIA), solid-phase direct or indirect enzyme immunoassays (EIA), sandwich competitive assays (e.g., Stahl et al., 1983, Methods in Enzymology 9:242-253); solid-phase direct biotin-avidin EIA (e.g., Kirkland et al., 1986, J. Immunol. 137:3614-3619); solid-phase direct label assays; solid-phase direct label sandwich assays (see, e.g., Harlow and Lane, 1988, Antibodies, A Laboratory Manual, Cold Spring Harbor Press); 125 Solid-phase direct labeling RIA (see, e.g., Morel et al., 1988, Molec. Immunol. 25:7-15); solid-phase direct biotin-avidin EIA (see, e.g., Chung et al., 1990, Virology 176:546-552); and direct labeling RIA (Moldenhauer et al., 1990, Scand. J. Immunol.) using a label can be used.

[0136] Typically, such assays involve the use of purified antigen bound to a solid surface or cells bearing either of these, an unlabeled test antigen-binding protein, and a labeled reference antibody. Competitive inhibition is measured by determining the amount of label bound to the solid surface or cells in the presence of the test antibody. The test antibody is usually present in excess. Antibodies identified by competitive assays (competing antibodies) include antibodies that bind to the same epitope as the reference antibody and antibodies that bind to an adjacent epitope sufficiently close to the epitope bound by the reference antibody so as to sterically hinder it. In some embodiments, when a competing antibody is present in excess, it will inhibit specific binding of the reference antibody to a common antigen by at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%. In some instances, binding is inhibited by at least 80%, 85%, 90%, 95%, or 97% or more.

[0137] The term "antigen" refers to a molecule or portion of a molecule that is capable of being bound by a selective binding agent, such as an antibody or an immunologically functional fragment thereof, and that can be used to raise antibodies in a mammal that are capable of binding to that antigen. An antigen may have one or more epitopes that are capable of interacting with an antibody.

[0138] The term "epitope" refers to the portion of an antigen molecule that is bound by a selective binding agent, such as an antibody or fragment thereof. The term includes any determinant capable of specific binding to an antibody. Epitopes can be contiguous or discontinuous (e.g., in a polypeptide, amino acid residues that are not contiguous with one another within the polypeptide sequence but that are bound by an antigen-binding protein within the context of the molecule). In some embodiments, an epitope can be mimetic in that it comprises a three-dimensional structure similar to the epitope used to generate antibodies, but contains none or only some of the amino acid residues found in the epitope used to generate antibodies. Epitopic determinants may include chemically active surface groups such as amino acids, sugar side chains, phosphoryl or sulfonyl groups, and may have specific three-dimensional structural characteristics, and / or specific charge characteristics.

[0139] In some embodiments, an "epitope" is defined by the method used to determine it. For example, in some embodiments, an antibody binds to the same epitope as a reference antibody if it binds to the same region of the antigen as determined by hydrogen-deuterium exchange (HDX).

[0140] In certain embodiments, an antibody binds to the same epitope as a reference antibody if it binds to the same region of the antigen as determined by x-ray crystallography.

[0141] As used herein, a "chimeric antibody" refers to an antibody that comprises at least one variable region derived from a first species (e.g., mouse, rat, cynomolgus monkey, etc.) and at least one constant region derived from a second species (e.g., human, cynomolgus monkey, chicken, etc.). In some embodiments, a chimeric antibody comprises at least one murine variable region and at least one human constant region. In some embodiments, all of the variable regions of a chimeric antibody are derived from a first species and all of the constant regions of the chimeric antibody are derived from a second species.

[0142] As used herein, "humanized antibody" refers to an antibody in which at least one amino acid in the framework region of a non-human variable region (e.g., mouse, rat, cynomolgus monkey, chicken, etc.) has been replaced with the corresponding amino acid from a human variable region. In some embodiments, a humanized antibody comprises at least one human constant region or a fragment thereof. In some embodiments, the humanized antibody fragment is a Fab, scFv, (Fab')2, etc.

[0143] As used herein, "CDR-grafted antibody" refers to a humanized antibody in which one or more complementarity-determining regions (CDRs) of a first species (non-human) have been grafted onto framework regions (FRs) of a second species (human).

[0144] As used herein, "human antibody" refers to antibodies produced in humans, antibodies produced in non-human animals carrying human immunoglobulin genes, such as XENOMOUSE®, and antibodies selected using in vitro methods, such as phage display, where the antibody repertoire is based on human immunoglobulin sequences.

[0145] "Host cell" refers to a cell that can be or has been a recipient of a vector or an isolated polynucleotide. Host cells can be prokaryotic or eukaryotic. Exemplary eukaryotic cells include mammalian cells, such as primate or non-primate cells; fungal cells, such as yeast; plant cells; and insect cells. Non-limiting exemplary mammalian cells include, but are not limited to, NSO cells, PER.C6® cells (Crucell), and 293 and CHO cells, and their derivatives, such as 293-6E and DG44 cells, respectively.

[0146] As used herein, the term "isolated" refers to a molecule that is separated from at least some of the components with which it is normally found in nature or from at least some of the components from which it is normally produced. For example, a polypeptide is said to be "isolated" when it is separated from at least some of the components of the cell in which it is produced. If a polypeptide is secreted from a cell after expression, physically separating the supernatant containing the polypeptide from the cell that produced it is considered to "isolate" the polypeptide. Similarly, a polynucleotide is said to be "isolated" if it is not part of a larger polynucleotide with which it is normally found in nature (e.g., in the case of a DNA polynucleotide, genomic DNA or mitochondrial DNA, etc.) or, for example, in the case of an RNA polynucleotide, if it is separated from at least some of the components of the cell in which it is produced. Thus, a DNA polynucleotide contained in a vector within a host cell may be said to be "isolated" so long as the polynucleotide is not found in that vector in nature.

[0147] As used herein, the terms "subject" and "patient" are used interchangeably to refer to mammals, such as humans. In some embodiments, methods of treating other non-human mammals, including but not limited to rodents, apes, felines, canines, horses, cows, pigs, sheep, goats, mammalian laboratory animals, mammalian farm animals, mammalian sport animals, and mammalian pets, are also provided. In some examples, "subject" or "patient" refers to a (human) subject or patient in need of treatment for a disease or disorder.

[0148] As used herein, the term "subject" or "patient subject" refers to material obtained or derived from a subject of interest, including cells and / or other molecular entities that are to be characterized and / or identified based on physical, biochemical, chemical, and / or physiological properties. For example, the phrase "disease sample" and variations thereof refers to any sample obtained from a subject that is suspected or known to contain cells and / or molecular entities that are to be characterized.

[0149] "Tissue or cell sample" refers to a collection of similar cells obtained from a subject's or patient's tissue. The source of the tissue or cell sample can be solid tissue, such as a fresh, frozen, and / or preserved organ or tissue sample or biopsy or aspirate; blood or any blood component; bodily fluid, such as sputum, cerebrospinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; or cells from any stage in a subject's pregnancy or development. The tissue sample can also be primary cells or cultured cells or cell lines. Optionally, the tissue or cell sample is obtained from a diseased tissue / organ. The tissue sample can contain compounds not naturally associated with tissue, such as preservatives, anticoagulants, buffers, fixatives, nutrients, or antibiotics.

[0150] As used herein, a "reference sample," "reference cell," or "reference tissue" refers to a sample, cell, or tissue obtained from a source known or believed to be free of the disease or condition for which the methods or compositions of the present invention are used to identify. In one embodiment, the reference sample, reference cell, or reference tissue is obtained from a healthy part of the body of the same subject or patient for whom the compositions or methods of the present invention are being used to identify the disease or condition. In one embodiment, the reference sample, reference cell, or reference tissue is obtained from a healthy part of the body of at least one individual who is not the subject or patient for whom the compositions or methods of the present invention are being used to identify the disease or condition. In some embodiments, the reference sample, reference cell, or reference tissue is previously obtained from the patient before the onset of the disease or condition, or at an earlier stage of the disease or condition.

[0151] A "disorder" or "disease" is any condition that would benefit from treatment with one or more IGSF8 antagonists of the present invention. This includes chronic and acute disorders or diseases, including those pathological conditions that predispose a mammal to the disorder in question. Non-limiting examples of disorders to be treated herein include cancer.

[0152] As used herein, the term "cancer" refers to a group of cells that exhibit an abnormally high level of proliferation and growth. Cancers may be benign (also called benign tumors), pre-malignant, or malignant. Cancer cells may be solid cancer cells (i.e., form solid tumors) or leukemia cancer cells. As used herein, the term "cancer growth" refers to proliferation or growth by cancer-containing cells, resulting in a corresponding increase in the size or extent of the cancer. A "chemotherapeutic agent" is a compound that may be useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and CYTOXAN® cyclophosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, metudopa, and uredopa; ethylenimines and methylmelamines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; acetogenins (particularly bullatacin and bullatacinone); camptothecins (including the synthetic analog topotecan); bryostatin; kallistatin; CC-1065 (including its synthetic analogs adozelesin, carzelesin, and bizelesin); cryptophycins (particularly cryptophycin 1 and cryptophycin 2); antibiotics such as toficin 8), dolastatins, duocarmycins (including synthetic analogs KW-2189 and CB1-TM1), eleutherobin, pancratistatin, sarcodictine, spongistatin, chlorambucil, chlornaphazine, colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembine, phenesterine, prednimustine, trofosfamide, nitrogen mustards such as uracil mustard, nitrosoreas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine, enediine antibiotics (e.g., calicheamicins, particularly calicheamine omegamol and calicheamine omegamol (e.g., Agnew, Chem. Intl. Ed. Engl., 33, 183-186 (1994)), dynemicins, including dynemicin A, bisphosphonates such as clodronate, esperamicin, and neocarzinostatin chromophore and related chromoprotein enediine antibiotic chromophores), aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® doxorubicin (morpholino-doxorubicin,including cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin, puromycin, chelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimec antimetabolites such as thiazolinone, zinostatin, zorubicin, methotrexate, and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxacin. Pyrimidine analogues such as thiazolidine, androgens such as calcisterone, dromostanone propionate, epitiostanol, mepitiostane, and testolactone, antiadrenergics such as aminoglutethimide, mitotane, and trilostane, folic acid supplements such as furoic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, and amsacrine; bestravcil, bisantrene, edatlaxate, defofamine, and demecolcine. Diazicon, elfomitin, elliptinium acetate, epothilone, etoglucide, gallium nitrate, hydroxyurea, lentinan, lonidynin, maytansinoids such as maytansine and ansamitocin, mitoguazone, mitoxantrone, mopidamol, nitraelin, pentostatin, phenamet, pirarubicin, losoxantrone, podophyllic acid, 2-ethylhydrazide, procarbazine, PSK® polysaccharide (JHS Natural Products, Eugene, OR), razoxane, rhizoxin, schizofiran, spirogermanium, tenuazonic acid, triazicon, 2,2',2"-trichlorotriethylamine. Trichothecenes (especially T-2 toxin, veracrine A, roridin A, and anguidin), urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman. Gacytosine, arabinoside ("Ara-C"),Cyclophosphamide, thiotepa, taxoids such as TAXOL® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Illinois), and TAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France), chlorambucil, GEMZAR® gemcitabine, 6-thioguanine, mercaptopurine, methotrexate, platinum analogs such as cisplatin, oxaliplatin, and carboplatin, vinblastine, platinum, etoposide (VP-16), ifosfamide, mitoxantrone, vincristine, NAVELBINE® vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, Xeloda, ibandronate, irinotecan (Camptosar, CPT-11) (Iri These include, but are not limited to, the topoisomerase inhibitor RFS2000, difluoromethylornithine (DMFO), retinoids such as retinoic acid, capecitabine, combretastatin, leucovorin (LV), oxaliplatin, including the oxaliplatin treatment regimen (FOLFOX), inhibitors of PKC-α, Raf, H-Ras, EGFR (e.g., erlotinib (TARCEVA®)) and VEGF-A that reduce cell proliferation, and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0153] Further non-limiting exemplary chemotherapeutic agents include antihormonal agents that act to regulate or inhibit hormone action on cancer, such as antiestrogens and selective estrogen receptor modulators (SERMs), e.g., tamoxifen (including NOLVADEX® tamoxifen), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, and FARESTON® toremifene, aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, e.g., 4(5)-imidazole, aminoglutethimide, MEGASE® megestrol acetate, AROMASIN® exemestane, formestany, fadrozole, RIVISOR® vorozole, FEMARA® letrozole, and ARIMIDEX® anastozole. antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin, and troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); antisense oligonucleotides, particularly those that inhibit the expression of genes in signaling pathways involved in abnormal cell growth, such as PKC-α, Ralf, and H-Ras; ribozymes (e.g., ANGIOZYME® ribozymes), such as VEGF expression inhibitors, and HER2 expression inhibitors; gene therapy vaccines, such as ALLOVECTIN® vaccine, LEUVECTIN® vaccine, and VAXID® vaccine; PROLEUKIN® rIL-2; LURTOTECAN® topoisomerase 1 inhibitors; ABARELIX® rmRH; and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0154] "Anti-angiogenic agents" or "angiogenesis inhibitors" refer to low molecular weight substances, polynucleotides (including, for example, inhibitory RNA (RNAi or siRNA)), polypeptides, isolated proteins, recombinant proteins, antibodies, or conjugates or fusion proteins thereof, that inhibit angiogenesis, vasculogenesis, or undesirable vascular permeability, either directly or indirectly. It should be understood that anti-angiogenic agents include agents that bind to and block the angiogenic activity of angiogenic factors or their receptors. For example, anti-angiogenic agents are antibodies or other antagonists to angiogenic agents, such as antibodies to VEGF-A (e.g., bevacizumab (AVASTIN®)) or antibodies to VEGF-A receptors (e.g., KDR receptors or Flt-1 receptors), anti-PDGFR inhibitors such as GLEEVEC® (imatinib mesylate), small molecules that block VEGF receptor signaling (e.g., PTK787 / ZK2284, SU6668, SUTENT® / SU11248 (sunitinib malate), AMG706, or those described, for example, in International Patent Application WO 2004 / 113304). Anti-angiogenic agents also include native angiogenesis inhibitors, such as angiostatin, endostatin, and the like. See, e.g., Klagsbrun and D'Amore (1991) Annu. Rev. Physiol. 53:217-39; Streit and Detmar (2003) Oncogene 22:3172-3179 (e.g., Table 3 listing antiangiogenic therapies in malignant melanoma); Ferrara & Alitalo (1999) Nature Medicine 5(12):1359-1364; Tonini et al. (2003) Oncogene 22:6549-6556 (e.g., Table 2 listing known antiangiogenic factors); and Sato (2003) Int. J. Clin. Oncol. 8:200-206 (e.g., Table 1 listing angiogenic agents used in clinical trials).

[0155] As used herein, a "growth inhibitor" refers to a compound or composition that inhibits cell proliferation (e.g., cells expressing VEGF) in vitro or in vivo. Thus, an example of a growth inhibitor may be one that significantly reduces the proportion of cells in S phase (e.g., cells expressing VEGF). Examples of growth inhibitors include, but are not limited to, agents that block cell cycle progression (at a location other than S phase), such as agents that induce G1 arrest and M-phase arrest. Classical M-phase blockers include vincas (vincristine and vinblastine), taxanes, and topoisomerase II inhibitors such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin. These agents that arrest G1 also extend to S-phase arrest, e.g., DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C. Further information can be found, for example, on page 13, in The Molecular Basis of Cancer, edited by Mendelsohn and Israel, Chapter 1, Title: "Cell cycle regulation, oncogenes, and antitineoplastic drugs" by Murakami et al. (WB Saunders, Philadelphia, 1995). Taxanes (paclitaxel and docetaxel) are anticancer drugs, both derived from the yew tree. Docetaxel (TAXOTERE®, Rhone-Poulenc Rorer) is derived from the European yew tree and is a semisynthetic analog of paclitaxel (TAXOL®, Bristol-Myers Squibb). Paclitaxel and docetaxel promote the assembly of microtubules from tubulin dimers, prevent depolymerization, and stabilize microtubules, thereby inhibiting mitosis in cells.

[0156] The term "antineoplastic composition" refers to a composition useful for treating cancer, comprising at least one active therapeutic agent. Examples of therapeutic agents include, for example, chemotherapeutic agents, growth inhibitory agents, cytotoxic agents, agents used in radiation therapy, anti-angiogenic agents, cancer immunotherapeutic agents (also called immuno-oncology agents), apoptotic agents, anti-tubulin agents, and other agents for treating cancer, such as anti-HER-2 antibodies, anti-CD20 antibodies, epidermal growth factor receptor (EGFR) antagonists (e.g., tyrosine kinase inhibitors), HER1 / EGFR inhibitors (e.g., erlotinib (TARCEVA®)), platelet-derived growth factor inhibitors (e.g., GLEEVEC® (imatinib mesylate)), COX2 inhibitors (e.g., celecoxib), interferons, CTLA4 inhibitors (e.g., anti-CTLA antibody I). These include, but are not limited to, pilimumab (YERVOY®), PD-1 inhibitors (e.g., anti-PD1 antibodies, BMS-936558), PDL1 inhibitors (e.g., anti-PDL1 antibodies, MPDL3280A), PDL2 inhibitors (e.g., anti-PDL2 antibodies), VISTA inhibitors (e.g., anti-VISTA antibodies), cytokines, antagonists (e.g., neutralizing antibodies) that bind to one or more of the following targets: ErbB2, ErbB3, ErbB4, PDGFR-β, BlyS, APRIL, BCMA, PD-1, PDL1, PDL2, CTLA4, VISTA, or VEGF receptors, TRAIL / Apo2, and other bioactive agents and organic chemical agents. Combinations thereof are also encompassed by the present invention.

[0157] "Treatment" refers to therapeutic treatment, where, for example, the objective is to slow (alleviate) the targeted condition or disorder, as well as to inhibit the recurrence of the condition or disorder. "Treatment" encompasses any administration or application of a therapeutic agent to a disease (also referred to herein as a "disorder" or "condition") in a mammal, including a human, and includes suppressing or slowing the disease or its progression, preventing its onset, partially or completely alleviating the disease, partially or completely alleviating one or more symptoms of the disease, or restoring or repairing lost, deficient, or defective function, or stimulating an inefficient process. The term "treatment" also includes reducing the severity of any phenotypic characteristic and / or reducing the incidence, degree, or likelihood of the characteristic. Those in need of treatment include those already with the disorder as well as those at risk of recurrence of the disorder or those in whom recurrence of the disorder is to be prevented or slowed.

[0158] The term "effective amount" or "therapeutically effective amount" refers to an amount of an agent effective in treating a disease or disorder in a subject. In some embodiments, an effective amount refers to the dosage and duration necessary to achieve the desired therapeutic or prophylactic result. The therapeutically effective amount of the IGSF8 antagonist of the present invention may vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the antagonist to elicit a desired response in the individual. A therapeutically effective amount encompasses an amount in which any damaging or adverse effects of the IGSF8 antagonist are outweighed by the therapeutically beneficial effects.

[0159] A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Generally, although not necessarily, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[0160] A "pharmaceutically acceptable carrier" refers to a non-toxic solid, semi-solid, or liquid filler, diluent, encapsulating material, formulation aid, or carrier conventionally used in the art for use with a therapeutic agent that together constitutes a "pharmaceutical composition" for administration to a subject. A pharmaceutically acceptable carrier is non-toxic to a recipient at the dosage and concentration used and is compatible with the other ingredients of the formulation. A pharmaceutically acceptable carrier is appropriate for the formulation used. For example, if the therapeutic agent is administered orally, the carrier may be a gel capsule. If the therapeutic agent is administered subcutaneously, the carrier ideally is non-irritating to the skin and does not cause injection site reactions.

[0161] An "article of manufacture" is any article of manufacture (e.g., package or container) or kit that includes at least one reagent, e.g., a medicament for treating a disease or disorder, or a probe for specifically detecting a biomarker described herein. In some embodiments, the article of manufacture or kit is advertised, distributed, or sold as a unit for performing a method described herein.

[0162] 3. How to treat cancer The invention described herein provides modulators, e.g., antagonists, to IGSF8 (e.g., isolated or recombinant monoclonal antibodies or antigen-binding fragments thereof specific for IGSF8) and its receptors (e.g., KIR3DL1 / 2, KLRC1 / D1) for use in methods of treating humans and other non-human mammals, e.g., animal models of cancer.

[0163] In one aspect, the invention provides a method of modulating an immune response in a subject in need thereof, comprising inhibiting the interaction between IGSF8 and a receptor for IGSF8 selected from KIR3DL1, KIR3DL2, and the KLRC1 / D2 heterodimer. In certain embodiments, the method comprises administering to the subject an anti-IGSF8 monoclonal antibody of the invention or an antigen-binding fragment thereof (such as those described herein).

[0164] In another aspect, the present invention provides a method of immunotherapy for treating cancer in a subject in need thereof, comprising inhibiting the interaction between IGSF8 and a receptor for IGSF8 selected from KIR3DL1, KIR3DL2, and the KLRC1 / D2 heterodimer. In certain embodiments, the method comprises administering to the subject an anti-IGSF8 monoclonal antibody of the present invention or an antigen-binding fragment thereof (such as those described herein).

[0165] In yet another aspect, the present invention provides a method for treating or preventing cancer in a subject in need thereof, comprising administering to a subject in need of such treatment a therapeutically effective amount of a modulator of IGSF8, KIR3DL1 / 2, or KLRC1 / D1 of the present invention (e.g., an antagonist such as an antibody or antigen-binding portion / fragment thereof).

[0166] Specifically, the present invention provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an IGSF8 (immunoglobulin superfamily 8) modulator (e.g., antagonist).

[0167] The present invention also provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a KIR3DL1 antagonist that inhibits its interaction with IGSF8.

[0168] The present invention further provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a KIR3DL2 antagonist that inhibits its interaction with IGSF8.

[0169] The present invention further provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a KLRC1 / D1 antagonist that inhibits interaction with IGSF8.

[0170] In some embodiments, methods of treating cancer are provided, comprising administering to a subject having cancer in need of treatment an effective amount of an IGSF8, KIR3DL1 / 2 or KLRC1 / D1 modulator (e.g., an antagonist, e.g., an antibody or antigen-binding portion / fragment) of the present invention.

[0171] In some embodiments, there is provided the use of an effective amount of an IGSF8, KIR3DL1 / 2 or KLRC1 / D1 modulator (e.g., an antagonist such as an antibody or antigen-binding portion / fragment thereof) of the present invention to treat cancer.

[0172] Non-limiting exemplary cancers that can be treated with an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) are provided herein and include carcinoma, lymphoma, embryonal tumor, sarcoma, and leukemia. More specific non-limiting examples of such cancers include melanoma, cervical cancer, squamous cell carcinoma, small cell lung cancer, pituitary cancer, esophageal cancer, astrocytoma, soft tissue sarcoma, non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, glioblastoma, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, brain cancer, endometrial cancer, testicular cancer, bile duct cancer, gallbladder cancer, gastric cancer, melanoma, and various head and neck cancers.

[0173] In certain embodiments, cancers treatable by the methods of the present invention using the IGSF8, KIR3DL1 / 2, or KLRC1 / D1 modulators (e.g., antagonists such as antibodies or antigen-binding portions / fragments) of the present invention include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More specific, non-limiting examples of such cancers include squamous cell carcinoma, small cell lung cancer, pituitary cancer, esophageal cancer, astrocytoma, soft tissue sarcoma, non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung, cancer of the peritoneum, hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, brain cancer, endometrial cancer, testicular cancer, cholangiocarcinoma, gallbladder cancer, stomach cancer, melanoma, and various head and neck cancers.

[0174] Additional treatable cancers include melanoma (including cutaneous melanoma of the skin), cervical cancer, lung cancer (e.g., non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma), colon cancer, lymphoma (including B-cell lymphoma and DLBCL), leukemia (including CLL and acute myeloid leukemia (AML)), BLCA tumors, breast cancer, head and neck carcinoma, head and neck squamous cell carcinoma, PRAD, THCA, or UCEC, thyroid cancer, urinary tract cancer, uterine cancer, esophageal cancer, liver cancer, or ganglionic carcinoma, kidney cancer, pancreatic cancer, pancreatic ductal carcinoma, ovarian cancer, prostate cancer, glioma, glioblastoma, neuroblastoma, thymoma, B-CLL, and cancers infiltrated with immune cells that express a receptor for IGSF8.

[0175] In certain embodiments, the treatable cancer is lung cancer, kidney cancer, pancreatic cancer, colon cancer, acute myeloid leukemia (AML), head and neck carcinoma, liver cancer, ovarian cancer, prostate cancer, or uterine cancer.

[0176] In some embodiments, the lung cancer is non-small cell lung cancer or squamous cell lung cancer.

[0177] In some embodiments, the leukemia is acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL).

[0178] In some embodiments, the breast cancer is invasive breast cancer.

[0179] In some embodiments, the ovarian cancer is ovarian serous cystadenocarcinoma.

[0180] In some embodiments, the kidney cancer is clear cell renal carcinoma.

[0181] In some embodiments, the colon cancer is a colon adenocarcinoma.

[0182] In some embodiments, the bladder cancer is bladder urothelial carcinoma.

[0183] In some embodiments, cancer cells and / or tumor immune infiltrating cells in a subject express IGSF8.

[0184] Without wishing to be bound by any particular theory, the methods of the present invention involve the use of NK cells and / or (CD8 + The present invention may be based on at least partially alleviating IGSF8-mediated inhibition of the host innate / adaptive immune system on effector cells of the host innate / adaptive immune system, such as T cells. Such inhibition may be brought about by IGSF8 binding to one or more IGSF8 receptors (e.g., KIR3DL1 / 2 and KLRC1 / D1), and such inhibition may be at least partially alleviated by inhibiting IGSF8 binding to these receptors expressed on effectors of the host innate / adaptive immune system (e.g., NK cells or T cells). Thus, the methods of the present invention may not rely on (but do not necessarily exclude) conventional ADCC- or CDC-mediated killing of target cells by innate immune system cells (e.g., NK cells) based on antibodies on the surface of these target cells that overexpress one of the IGSF8 receptors (e.g., KIR3DL1 / 2 and KLRC1 / D1).

[0185] Thus, in some embodiments, cancer is treatable by inhibiting the binding between IGSF8 and at least one of its receptors, such as KIR3DL1 / 2 and KLRC1 / D1. In some embodiments, the cancer expresses IGSF8. See, for example, any of the cancers listed in Figure 6A, 6B, or 6C, which show IGSF8 expression.

[0186] In some embodiments, the cancer is not characterized by expression or overexpression of KIR3DL1 / 2. In some embodiments, the cancer is characterized by Sézary syndrome, CD30 + Not cutaneous lymphoma or cutaneous T-cell lymphoma such as transformed mycosis fungoides.

[0187] In some embodiments, the cancer is not characterized by expression or overexpression of KLRC1 / D1.

[0188] In some embodiments, the KIR3DL1 antagonist is selected from an anti-KIR3DL1 antibody or an antigen-binding portion / fragment thereof, a KIR3DL1 inhibitory peptide, a nucleic acid targeting KIR3DL1 (aptamer, antisense polynucleotide, RNAi reagent such as siRNA, miRNA, shRNA; guide RNA for type 2 CRISPR / Cas effector enzyme), or a small molecule targeting KIR3DL1 (e.g., molecular weight <1000 Da or <500 Da); optionally, the KIR3DL1 antagonist is an anti-KIR3DL1 antibody or an antigen-binding portion / fragment thereof.

[0189] In some embodiments, the KIR3DL2 antagonist is selected from an anti-KIR3DL2 antibody or an antigen-binding portion / fragment thereof, a KIR3DL2 inhibitory peptide, a nucleic acid targeting KIR3DL2 (aptamer, antisense polynucleotide, RNAi reagent such as siRNA, miRNA, shRNA; guide RNA for type 2 CRISPR / Cas effector enzyme), or a small molecule targeting KIR3DL2 (e.g., molecular weight <1000 Da or <500 Da); optionally, the KIR3DL2 antagonist is an anti-KIR3DL2 antibody or an antigen-binding portion / fragment thereof.

[0190] In some embodiments, the anti-KIR3DL1 / 2 antibody or its antigen-binding portion / fragment, inhibitory peptide against KIR3DL1 / 2, nucleic acid targeting KIR3DL1 / 2, or small molecule targeting KIR3DL1 / 2 binds to an epitope of KIR3DL1 / 2 comprising residues S165, I171, and / or M186, thereby inhibiting IGSF8 binding to the D2 domain of KIR3DL1 / 2.

[0191] In some embodiments, the anti-KIR3DL1 / 2 antibody or antigen-binding portion / fragment thereof specifically binds to the middle / D2 Ig-like domain of the ECD of KIR3DL1 / 2, and optionally, the anti-KIR3DL1 / 2 antibody or antigen-binding portion / fragment thereof specifically binds to an epitope comprising residues S165, I171, and / or M186.

[0192] In some embodiments, the KLRC1 / D1 antagonist is selected from an anti-KLRC1 / D1 antibody or an antigen-binding portion / fragment thereof, a KLRC1 / D1 inhibitory peptide, a nucleic acid targeting KLRC1 / D1 (aptamer, antisense polynucleotide, RNAi reagent such as siRNA, miRNA, shRNA; guide RNA for type 2 CRISPR / Cas effector enzyme), or a small molecule targeting KLRC1 / D1 (e.g., molecular weight <1000 Da or <500 Da); optionally, the KLRC1 / D1 antagonist is an anti-KLRC1 / D1 antibody or an antigen-binding portion / fragment thereof.

[0193] In some embodiments, the IGSF8 antagonist is selected from an anti-IGSF8 antibody or an antigen-binding portion / fragment thereof, an IGSF8 inhibitory peptide, a nucleic acid targeting IGSF8 (aptamer, antisense polynucleotide, RNAi reagent such as siRNA, miRNA, shRNA; guide RNA for type 2 CRISPR / Cas effector enzyme), or a small molecule targeting IGSF8 (e.g., molecular weight <1000 Da or <500 Da); optionally, the IGSF8 antagonist is an anti-IGSF8 antibody or an antigen-binding portion / fragment thereof.

[0194] In some embodiments, the IGSF8 antagonist is selected from an anti-IGSF8 antibody or antigen-binding fragment thereof. In some embodiments, the antibody is a chimeric antibody, a humanized antibody, or a human antibody. In some embodiments, the anti-IGSF8 antibody or antigen-binding fragment thereof binds to the terminal Ig-V set ECD or D1 of IGSF8. In some embodiments, the anti-IGSF8 antibody or antigen-binding fragment thereof inhibits IGSF8 binding to an epitope including the middle / D2 domain of KIR3DL1 / 2, e.g., KIR3DL1 and / or KIR3DL2, e.g., residues S165, I171, and / or M186 of KIR3DL1 / 2.

[0195] In some embodiments, the antigen-binding portion / fragment is a Fab, Fab', F(ab'), Fd , single-chain Fv or scFv, disulfide-linked F v , V-NAR domain, IgNar, intrabody, IgGΔCH2, minibody, F(ab')3, tetrabody, triabody, diabody, single domain antibody, DVD-Ig, Fcab, mAb2, (scFv)2 or scFv-FC.

[0196] In some embodiments, the anti-IGSF8 antibody or antigen-binding portion / fragment thereof is any one of the monoclonal antibodies or antigen-binding portion / fragment thereof described herein (see the section on IGSF8 antagonists, e.g., anti-IGSF8 antibodies).

[0197] In some embodiments, the IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) promotes expression, secretion, or otherwise increases the activity of a cytokine or target gene selected from the group consisting of CXCL10, CXCL9, TNFα, CD8b, CD8a, Prf1, IFNγ, Gzma, Gzmb, CD274, PDCD1, PDCD1 Ig2, LAG3, Havcr2, Tigit, or CTLA4.

[0198] In some embodiments, the increased expression, secretion, or other activity of the cytokine or the target gene occurs within the tumor microenvironment.

[0199] In some embodiments, the increased expression, secretion, or other activity of the cytokine or the target gene results from the infiltration of immune cells (e.g., T lymphocytes or NK cells) into the tumor microenvironment.

[0200] In some embodiments, the anti-IGSF8 and / or anti-KIR3DL1 / 2 and / or anti-KLRC1 / D1 antibody or antigen-binding portion / fragment thereof is conjugated to a cytotoxic agent, which may be selected from the group consisting of a chemotherapeutic agent, a biologic agent, a toxin, and a radioisotope.

[0201] In some embodiments, the IGSF8 antagonist, KIR3DL1 antagonist, KIR3DL2 antagonist, or KLRC1 / D1 antagonist is an immunostimulatory molecule.

[0202] In some embodiments, the IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention), KIR3DL1 antagonist, KIR3DL2 antagonist, or KLRC1 / D1 antagonist stimulates the activation and / or infiltration of T cells or NK cells into the tumor microenvironment.

[0203] In some embodiments, the anti-IGSF8 and / or anti-KIR3DL1 / 2 and / or anti-KLRC1 / D1 antibodies or antigen-binding portions / fragments thereof reduce the number of proliferating cells in a cancer and / or reduce the volume or size of a cancer tumor.

[0204] In some embodiments, the anti-IGSF8 and / or anti-KIR3DL1 / 2 and / or anti-KLRC1 / D1 antibodies or antigen-binding portions / fragments thereof are administered in a pharmaceutically acceptable formulation.

[0205] In some embodiments, the anti-IGSF8 antibody or antigen-binding fragment thereof (e.g., F(ab')2 fragment) is administered in combination with a second therapeutic agent (see the Combination Therapy section, incorporated herein by reference).

[0206] In some embodiments, the anti-IGSF8, anti-KIR3DL1 / 2, or anti-KLRC1 / D1 antibody or antigen-binding fragment thereof is administered in conjunction with a second immune checkpoint inhibitor, e.g., an immune checkpoint inhibitor that restores or enhances T cell-mediated immunotherapy.

[0207] In some embodiments, the immune checkpoint inhibitor is an antibody or antigen-binding fragment thereof specific for PD-1, PD-L1, PD-L2, LAG3, TIGIT, TIM3, NKG2A, CD276, VTCN1, VISR, or HHLA2.

[0208] In some embodiments, an anti-IGSF8, anti-KIR3DL1 / 2, or anti-KLRC1 / D1 antibody or antigen-binding fragment thereof is administered in combination with an anti-PD-1 antibody or antigen-binding fragment thereof, an anti-PD-L1 antibody or antigen-binding fragment thereof, and / or an anti-CTLA-4 antibody or antigen-binding fragment thereof. In some embodiments, the anti-IGSF8 antibody is a human antibody.

[0209] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody, such as cemiplimab, nivolumab, or pembrolizumab.

[0210] In some embodiments, the immune checkpoint inhibitor is an anti-PD-L1 antibody, such as avelumab, durvalumab, atezolizumab, KN035, or CK-301.

[0211] In some embodiments, the immune checkpoint inhibitor is a (non-antibody) peptide inhibitor of PD-1 / PD-L1, such as AUNP12; a small molecule inhibitor of PD-L1, such as CA-170, or a macrocyclic peptide, such as BMS-986189.

[0212] In certain embodiments, the combination therapy further comprises a therapeutic antibody effective to treat cancer or an immunological condition. Exemplary therapeutic antibodies include: 3F8, 8H9, abagovomab, abciximab, abirulumab, abrezekimab, abrilumab, actoxumab, adalimumab, adecatumumab, aducanumab, afacevicumab, afelimomab, alacizumab pegol, alemtuzumab, alirocumab, altumomab pentetate, amatuximab, amivantamab, anatumomab mafenatox, andecaliximab, anetumab ravtansine, anifrolumab, anrukinzumab, apolizumab, and apruzumab. Ixadotin, arcitumomab, asclinbacumab, acelizumab, atezolizumab, atidortoxumab, atinumab, atorolimumab, avelumab, azintuximab vedotin, bapineuzumab, basiliximab, bavituximab, BCD-100, bectumomab, begelomab, belantamab mafodotin, belimumab, bemarituzumab, benralizumab, berlimatoxumab, bermekimab, bersanlimab, bertilimumab, besilesomab, bevacizumab, bezlotoxumab, biciromab, bimagrumab, bimekiz Mab, viltamimab, bivatuzumab, bleselumab, blinatumomab, brontuzumab, brosozumab, bococizumab, brazikumab, brentuximab vedotin, briakinumab, brodalumab, brolucizumab, brontiximab, burosumab, cabilalizumab, camidanlumab tesirin, camrelizumab, canakinumab, cantuzumab mertansine, cantuzumab ravtansine, caplacizumab, capromab, carlumab, carotuximab, catumaxomab, cBR-doxorubicin immunoconjugate, sederi Zumab, cemiplimab, sergituzumab amnaleukin, certolizumab pegol, cetrelimab, cetuximab, civisatamab, cirumtuzumab, sitatuzumab bogatox, cixutumumab, clazakizumab, clenoliximab, clivatuzumab tetraxetan, codrituzumab, cofetuzumab peridotin, coltuximab ravtansine, conatumumab, concizumab, cosfrobiximab, crenezumab, crizanlizumab, clotedumab, CR6261, cusatuzumab, dacetuzumab, daclizumab, dalotuzumab,Dapirolizumab pegol, daratumumab, dectrecumab, demcizumab, denintuzumab mafodotin, denosumab, depatuxizumab mafodotin, dellotuximab biotin, detumomab, dezamizumab, dinutuximab, zilidabumab, domagrozumab, dorlimomab alitox, dostarlimab, drozitumab, DS-8201, durigotuzumab, dupilumab, durvalumab, dusigitumab, duvortuxizumab, ecromeximab, eculizumab, edovacomab, edrecolomab, efalizumab, efangumab, eldelumab, erezza Numab, elgemtumab, elotuzumab, elsilimomab, emactuzumab, emapalumab, emibetuzumab, emicizumab, enapotamab vedotin, enavatuzumab, enfortumab vedotin, enlimomab pegol, enoblitzumab, enokizumab, enoticumab, ensituximab, epitumomab cituxetan, epratuzumab, eptinezumab, erenumab, erlizumab, ertumaxomab, etaracizumab, etigilimab, etorolizumab, evinacumab, evolocumab, exbivirumab, fanolesomab, faralimomab, faricimab, Farletuzumab, fasinumab, FBTA05, felvizumab, fezakinumab, fibatuzumab, ficlatuzumab, figitumumab, filibumab, framvotumab, fretikumab, flotetuzumab, fontolizumab, foralumab, foravirumab, fremanezumab, fresolimumab, furobocimab, furunvetomab, furanumab, futuximab, galcanezumab, galiximab, gancotamab, ganitumab, gantenerumab, gatipotuzumab, gavirimomab, gezivumab, gemtuzumab ozogamicin, gevokizumab, zirvetumab, zim Cirumab, dilentuximab, glenbatumumab vedotin, golimumab, gomiliximab, goslanemab, guselkumab, ranalumab, ibalizumab, IBI308, ibritumomab tiuxetan, icrucumab, idarucizumab, ifavotuzumab, igovomab, iradatuzumab vedotin, IMAB363, imalumab, imaprelimab, imciromab, imgatuzumab, inlacumab, indatuximab vedotin, indusatumab vedotin, inebilizumab, infliximab, intetumumab, inolimomab, inotuzumab ozogamicin,Ipilimumab, Iomab-B, Iratumumab, Isatuximab, Iscalimab, Istiratumab, Itolizumab, Ixekizumab, Keliximab, Labetuzumab, Lacnotuzumab, Radilatuzumab vedotin, Lampalizumab, Lanadelumab, Landgrozumab, Laprituximab emtansine, Ralcabiximab, Lebrikizumab, Remaresomab, Lendarizumab, Lembervimab, Lenzilumab, Lerdelimumab, Leronlimab, Lesofabrumab, Letolizumab, Lexatumumab, Ribivirumab, Rifastuzumab vedotin, Ligelizumab, Lonca Stuximab tesirin, rosatuxizumab vedotin, rilotomab satetraxetan, lintuzumab, lirilumab, roderucizumab, loxivetumab, lorvotuzumab mertansine, lucatumumab, lurizumab pegol, rumiliximab, lumuletuzumab, rupartumab, rupartuzumab amadotin, rutikizumab, mapatumumab, marjetuximab, marstacimab, maslimomab, mavrilimumab, matuzumab, mepolizumab, metelimumab, milatuzumab, minletumomab, mirikizumab, mirvetuximab soravtansine, mitsumomab, modutuximab , mogamulizumab, monalizumab, morolimumab, mosunetuzumab, motavizumab, moxetumomab pasudotox, muromonab-CD3, nacolomab butafenatox, namilumab, naptumomab estafenatox, naratuximab emtansine, narutumab, natalizumab, nabicixizumab, nabibumab, naxitamab, nebacumab, necitumumab, nemolizumab, NEOD001, nerelimomab, nesbacumab, netakimab, nimotuzumab, nirsevimab, nivolumab, nofetumomab merpentane, obilutoxaximab, obinutuzumab , ocralatuzumab, ocrelizumab, odulimomab, ofatumumab, olaratumab, oleculumab, orendalizumab, olokizumab, omalizumab, omburtamab, OMS721, onartuzumab, ontuxizumab, ombatilimab, opicinumab, oportuzumab monatox, oregovomab, olticumab, otelixizumab, otilimab, otreltuzumab, oxelumab, ozanezumab, ozoralizumab, pasivaximab, palivizumab, pamrevlumab, panitumumab, pancomab, panobacumab, palsatuzumab, pascolizumab,pasotuximab, pateclizumab, patritumab, PDR001, pembrolizumab, pemtumomab, perakizumab, pertuzumab, pexelizumab, pidilizumab, pinatuzumab vedotin, pintumomab, placurumab, prezalumab, prozalizumab, pogalizumab, polatuzumab vedotin, ponezumab, polgabiximab, prasinezumab, prezalizumab, priliximab, pritoxaximab, pritumumab, PRO140, kilimab, racotumomab, radletumab, rafivirumab, ralpancizumab, ramucirumab, ranevetomab , ranibizumab, raxibacumab, ravagalimab, ravutolizumab, refanezumab, regavirumab, REGN-EB, leratolimab, lemtolumab, reslizumab, rilotumumab, rinukumab, risankizumab, rituximab, rivavazumab pegol, lobatumumab, Rmab, loredumab, romilkimab, romosozumab, lontalizumab, rosmantuzumab, rovalpituzumab tesirin, rovelizumab, rozanolixizumab, ruplizumab, SA237, sacituzumab govitecan, samalizumab, samlotamab vedotin, sarilumab, satralizumab, sa Tumomab pendetide, secukinumab, cericlerumab, seribantumab, cetoxaximab, setursumab, sevirumab, sibrotuzumab, SGN-CD19A, SHP647, sifalimumab, siltuximab, simtuzumab, siplizumab, siltratumab vedotin, sirukumab, sofituzumab vedotin, solanezumab, solitomab, sonepcizumab, sontuzumab, spartalizumab, stamulumab, sulesomab, sputabumab, stimulimab, subizumab, subratoxumab, tabalumab, tacatuzumab tetraxetan, tadocizumab, tarako Tuzumab, talizumab, talquetamab, tamtubetumab, tanezumab, taplitumomab paptox, talexuzumab, tabolimab, teclistamab, tefibazumab, terimomab alitox, telisotuzumab, telisotuzumab vedotin, tenatumomab, teneliximab, teplizumab, tepositamab, teprotumumab, tesidolumab, tetulomab, tezepelumab, TGN1412, tiburizumab, tildrakizumab, tigatuzumab, timigituzumab, timolumab, tiragolumab, tiragotumab, tislelizumab, tisotuzumab vedotin, TNX-650,Tocilizumab, tomzotuximab, toralizumab, tosatoxumab, tositumomab, tobetumab, tralokinumab, trastuzumab, trastuzumab duocarmazine, trastuzumab emtansine, TRBS07, tregalizumab, tremelimumab, trevoglumab, tucotuzumab celmoleukin, tuvilumab, ublituximab, urocupulumab, urelumab, urtoxazumab, ustekinumab, utomilumab, vadastuximab butarilin, vanalimab, vandaltuzumab vedotin, vandaltuzumab, vandaltuzumab Mab, bapaliximab, valisacumab, varlilumab, batelizumab, vedolizumab, veltuzumab, bepalimomab, besencumab, visilizumab, bovalilizumab, volociximab, bonlerolizumab, bopratelimab, borsetuzumab mafodotin, votumumab, bunakizumab, xentuzumab, XMAB-5574, zalutumumab, zanolimumab, zatuximab, zenoctuzumab, diralimumab, zolbetuximab, (=IMAB362, claudiximab), zolimomab alitox, or a combination thereof.

[0213] In certain embodiments, the second therapeutic agent comprises an antibody or antigen-binding portion / fragment thereof effective to induce ADCC, ADCP, and / or CDC.

[0214] In some embodiments, the IGSF8 antagonist for treating cancer may be a non-antibody protein, such as a soluble version of the IGSF8 protein or a portion thereof (e.g., an Ig-V set ECD) that inhibits the interaction between IGSF8 and its ligand, optionally further comprising a fusion partner, in the form of a fusion molecule such as an (IgG1)Fc fusion. Various exemplary IGSF8 antagonists are described in more detail in the following sections.

[0215] In some embodiments, the KIR3DL1 / 2 antagonist for treating cancer may be a non-antibody protein, for example, a soluble version of the KIR3DL1 / 2 protein or a portion thereof (e.g., the second Ig domain of the ECD) that inhibits the interaction between IGSF8 and KIR3DL1 / 2, optionally further comprising a fusion partner, in the form of a fusion molecule such as an (IgG1)Fc fusion.

[0216] In some embodiments, the KLRC1 / D1 antagonist for treating cancer may be a non-antibody protein, for example, a soluble version of the KLRC1 / D1 protein or a portion thereof (e.g., ECD) that inhibits the interaction between IGSF8 and KLRC1 / D1, optionally further comprising a fusion partner, in the form of a fusion molecule such as an (IgG1)Fc fusion.

[0217] The invention described herein also provides KIR3DL1 / 2 or KLRC1 / D1 antagonists for use in methods of treating humans and other non-human mammals.

[0218] In some embodiments, methods are provided for treating or preventing cancer, comprising administering to a subject in need of such treatment an effective amount of a KIR3DL1 / 2 or KLRC1 / D1 antagonist.

[0219] In some embodiments, methods are provided for activating NK cells, e.g., activating NK cell-mediated immunotherapy (which may be useful for treating or preventing cancer), comprising contacting NK cells with a KIR3DL1 / 2 or KLRC1 / D1 antagonist or administering an effective amount of a KIR3DL1 / 2 or KLRC1 / D1 antagonist to a subject in need of such NK cell-mediated immunotherapy.

[0220] In some embodiments, methods of treating cancer are provided, comprising administering a KIR3DL1 / 2 or KLRC1 / D1 antagonist to a subject with cancer.

[0221] In some embodiments, there is provided a use of a KIR3DL1 / 2 or KLRC1 / D1 antagonist for treating cancer.

[0222] In some embodiments, the cancer is treatable by inhibiting the binding between IGSF8 and KIR3DL1 / 2 and / or KLRC1 / D1. In some embodiments, the cancer expresses IGSF8. In some embodiments, the cancer is not characterized by expression or overexpression of KIR3DL1 / 2. In some embodiments, the cancer is characterized by Sézary syndrome, CD30 + It is not a cutaneous T-cell lymphoma, such as cutaneous lymphoma or transformed mycosis fungoides.

[0223] In some embodiments, the KIR3DL1 / 2 or KLRC1 / D1 antagonist is an anti-KIR3DL1 / 2 or anti-KLRC1 / D1 antibody, or an antigen-binding fragment thereof. In one embodiment, the KIR3DL1 / 2 or KLRC1 / D1 antagonist is an antibody or antibody-binding fragment thereof that specifically binds to KIR3DL1 / 2 or KLRC1 / D1 and inhibits IGSF8 binding to KIR3DL1 / 2 or KLRC1 / D1 (e.g., inhibits KIR3DL1 / 2-mediated IFNγ secretion in NK cells by at least about 20%, 40%, 50%, 60%, 80%, 90% or more). In one embodiment, the anti-KIR3DL1 / 2 or anti-KLRC1 / D1 antibody is a human antibody.

[0224] In certain embodiments, the anti-KIR3DL1 / 2 antibody or antigen-binding fragment thereof specifically binds to the D2 domain of KIR3DL1 / 2 and inhibits IGSF8 binding. In certain embodiments, the anti-KIR3DL1 / 2 antibody or antigen-binding fragment thereof specifically binds to an epitope within the D2 domain of KIR3DL1 / 2 and inhibits IGSF8 binding to residues S165, I171, and / or M186 of KIR3DL1 / 2. In one embodiment, the anti-KIR3DL2 antibody is not IPH4102.

[0225] In one embodiment, the KIR3DL1 / 2 antagonist is the extracellular domain (ECD) of IGSF8 that inhibits the binding of IGSF8 to KIR3DL1 / 2, for example, to residues S165, I171 and / or M186 of KIR3DL1 / 2, without inducing the inhibitory function of KIR3DL1 / 2 on NK cell activation, proliferation, and / or viability.

[0226] In one embodiment, the KIR3DL1 / 2 or KLRC1 / D1 antagonist is a small molecule that binds to KIR3DL1 / 2 or KLRC1 / D1 without inducing the inhibitory function of KIR3DL1 / 2 on NK cell activation, proliferation and / or viability, and inhibits the binding of IGSF8 to KIR3DL1 / 2 or KLRC1 / D1, for example, to residues S165, I171, and / or M186 of KIR3DL1 / 2.

[0227] In one embodiment, the KIR3DL1 / 2 antagonist is a CpG-oligodeoxynucleotide (CpG-ODN), which, upon binding to the first (or D1) Ig-like domain of the ECD of KIR3DL1 / 2, causes downregulation of KIR3DL1 / 2 from the cell surface and translocation to endosomes, delivering the CpG-ODN to Toll-like receptor 9 and activating NK cells.

[0228] In a related aspect, the present invention provides the use of an IGSF8 antagonist, a KIR3DL1 antagonist, a KIR3DL2 antagonist, or a KLRC1 / D1 antagonist that inhibits IGSF8 binding to a receptor of IGSF8 selected from KIR3DL1, KIR3DL2, and a KLRC1 / D2 heterodimer, for treating cancer in a subject.

[0229] In certain embodiments, the use is for combined use with any one or more of the second therapeutic agents described herein.

[0230] A related aspect of the present invention provides a composition comprising an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention), a KIR3DL1 antagonist, a KIR3DL2 antagonist, or a KLRC1 / D1 antagonist for use in any of the methods of the present invention described herein, wherein the composition inhibits binding of IGSF8 to its receptor selected from KIR3DL1, KIR3DL2, and KLRC1 / D2 heterodimers.

[0231] 4. Route of Administration and Carriers In various embodiments, the IGSF8 antagonist (eg, an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or KIR3DL1 / 2 antagonist and / or KLRC1 / D1 antagonist can be administered subcutaneously or intravenously.

[0232] In some embodiments, the IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or KIR3DL1 / 2 antagonist and / or KLRC1 / D1 antagonist can be administered in vivo by various routes, including, but not limited to, orally, intraarterially, parenterally, intranasally, intramuscularly, intracardially, intracerebroventricularly, intratracheally, buccally, rectally, intraperitoneally, by inhalation, intradermally, topically, transdermally, and intrathecally, or otherwise, for example, by implantation.

[0233] The subject compositions can be formulated in solid, semi-solid, liquid, or gaseous form, including, but not limited to, tablets, capsules, powders, granules, ointments, solutions, suppositories, enemas, injections, inhalants, and aerosols.

[0234] In some embodiments, the IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or the KIR3DL1 / 2 antagonist and / or the KLRC1 / D1 antagonist are delivered using gene therapy. As a non-limiting example, nucleic acid molecules (e.g., Cas9 and sgRNA, or Cas12a and crRNA) encoding the IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or the KIR3DL1 / 2 antagonist and / or the KLRC1 / D1 antagonist may be coated onto gold microparticles and delivered intradermally by a particle bombardment device or "gene gun," as described in the literature (see, e.g., Tang et al., Nature 356:152-154 (1992)).

[0235] In various embodiments, compositions containing IGSF8 antagonists (e.g., anti-IGSF8 monoclonal antibodies or antigen-binding fragments thereof of the present invention) and / or KIR3DL1 / 2 antagonists and / or KLRC1 / D1 antagonists are provided in the form of a formulation with various pharmaceutically acceptable carriers (see, for example, Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus, 20th Edition (2003); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition, Lippencott Williams and Wilkins (2004); Kibbe et al., Handbook of Pharmaceutical Excipients, 3rd Edition, Pharmaceutical Press (2000)). A variety of pharmaceutically acceptable carriers, including vehicles, adjuvants, and diluents, are available. Additionally, various pharmaceutically acceptable auxiliary substances may be utilized, such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents, etc. Non-limiting exemplary carriers include saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof.

[0236] In various embodiments, a composition comprising an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist may be formulated for injection, such as subcutaneous administration, by dissolving, suspending, or emulsifying it in an aqueous or non-aqueous solvent, such as a vegetable oil or other oil, a synthetic fatty acid glyceride, an ester of a higher fatty acid, or propylene glycol, together with conventional additives, such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives, as needed.

[0237] In various embodiments, the compositions may be formulated for inhalation using pressurized acceptable propellants such as dichlorodifluoromethane, propane, and nitrogen.

[0238] In various embodiments, the composition can also be formulated into sustained-release microcapsules using biodegradable or non-biodegradable polymers. Non-limiting exemplary biodegradable formulations include polylactic-co-glycolic acid (PLGA) polymers. Non-limiting exemplary non-biodegradable formulations include polyglycerol fatty acid esters. Specific methods for preparing such formulations are described, for example, in EP1125584A1.

[0239] Pharmaceutical dosage packs are also provided, each containing one or more containers containing one or more doses of an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist. In some embodiments, a unit dosage is provided, the unit dosage containing a predetermined amount of a composition comprising an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist, with or without one or more additional agents. In some embodiments, such a unit dose is supplied in a single-use pre-filled syringe for injection. In various embodiments, the composition contained in the unit dose may be formulated in a buffer, such as saline or sucrose, a phosphate, or the like, and / or within a stable and effective pH range. Alternatively, in some embodiments, the composition may be provided as a lyophilized powder that can be reconstituted by adding a suitable liquid, such as sterile water. In some embodiments, the composition includes one or more substances that inhibit protein aggregation, including, but not limited to, sucrose and arginine. In some embodiments, the composition of the present invention includes heparin and / or proteoglycan.

[0240] The pharmaceutical compositions are administered in an amount effective for treating or preventing a particular indication. A therapeutically effective amount typically depends on the weight of the subject being treated, their physical or health condition, the extent of the condition being treated, or the age of the subject being treated.

[0241] In some embodiments, the IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or KIR3DL1 / 2 antagonist and / or KLRC1 / D1 antagonist may be administered in an amount ranging from about 50 μg / kg to about 50 mg / kg of body weight per dose. In some embodiments, the IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or KIR3DL1 / 2 antagonist and / or KLRC1 / D1 antagonist may be administered in an amount ranging from about 100 μg / kg to about 50 mg / kg of body weight per dose. In some embodiments, the IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or KIR3DL1 / 2 antagonist and / or KLRC1 / D1 antagonist may be administered in an amount ranging from about 100 μg / kg to about 20 mg / kg of body weight per dose. In some embodiments, the IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or KIR3DL1 / 2 antagonist and / or KLRC1 / D1 antagonist may be administered in an amount ranging from about 0.5 mg / kg to about 20 mg / kg of body weight per dose.

[0242] In some embodiments, the IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or KIR3DL1 / 2 antagonist and / or KLRC1 / D1 antagonist may be administered in an amount ranging from about 10 mg to about 1,000 mg per dose. In some embodiments, the IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or KIR3DL1 / 2 antagonist and / or KLRC1 / D1 antagonist may be administered in an amount ranging from about 20 mg to about 500 mg per dose. In some embodiments, the IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or KIR3DL1 / 2 antagonist and / or KLRC1 / D1 antagonist may be administered in an amount ranging from about 20 mg to about 300 mg per dose. In some embodiments, the IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or KIR3DL1 / 2 antagonist and / or KLRC1 / D1 antagonist may be administered in an amount ranging from about 20 mg to about 200 mg per dose. The IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or KIR3DL1 / 2 antagonist and / or KLRC1 / D1 antagonist composition may be administered to a subject as needed. In some embodiments, an effective amount of the IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or KIR3DL1 / 2 antagonist and / or KLRC1 / D1 antagonist is administered to a subject one or more times. In various embodiments, an effective amount of the IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or KIR3DL1 / 2 antagonist and / or KLRC1 / D1 antagonist is administered to a subject monthly, less than monthly, for example, once every two months, once every three months, or once every six months, etc. In other embodiments, an effective amount of an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or a KIR3DL1 / 2 antagonist is administered more than once a month, for example, once every two weeks, once a week, twice a week, three times a week, once a day, or multiple times a day. An effective amount of an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist is administered to a subject at least once. In some embodiments, an effective amount of an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist may be administered multiple times over a period of at least one month, at least six months, or at least one year, etc. In some embodiments, an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist is administered to a subject on demand to alleviate one or more symptoms of the condition.

[0243] 5. Combination therapy The IGSF8 antagonists (e.g., the anti-IGSF8 monoclonal antibodies or antigen-binding fragments thereof) and / or KIR3DL1 / 2 antagonists and / or KLRC1 / D1 antagonists of the present invention include any antibodies and functional fragments thereof, and may be administered to a subject in need thereof in combination with other biologically active substances or other treatment procedures for the treatment of diseases. For example, the IGSF8 antagonists (e.g., the anti-IGSF8 monoclonal antibodies or antigen-binding fragments thereof) and / or KIR3DL1 / 2 antagonists and / or KLRC1 / D1 antagonists may be administered alone or together with other treatment modalities. They may be provided before, substantially simultaneously with, or after other treatment modalities, such as radiation therapy.

[0244] In some embodiments, the methods of the invention may include administering to the subject an effective amount of a second therapeutic agent comprising an immunotherapeutic agent, an immune checkpoint inhibitor, a cancer vaccine, a chimeric antigen receptor, a chemotherapeutic agent, a radiotherapeutic agent, an anti-angiogenic agent, a growth inhibitory agent, an immuno-oncology agent, an anti-neoplastic composition, surgery, or a combination thereof.

[0245] To treat cancer, the IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or KIR3DL1 / 2 antagonist and / or KLRC1 / D1 antagonist may be administered in combination with one or more anti-cancer agents, such as immune checkpoint inhibitors, chemotherapeutic agents, growth inhibitors, anti-angiogenic agents, or anti-neoplastic compositions.

[0246] In some embodiments, the immune checkpoint inhibitor is an antibody or antigen-binding fragment thereof specific for PD-1, PD-L1, PD-L2, LAG3, TIGIT, TIM3, NKG2A, CD276, VTCN1, VISR, or HHLA2.

[0247] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody, such as cemiplimab, nivolumab, or pembrolizumab.

[0248] In some embodiments, the immune checkpoint inhibitor is an anti-PD-L1 antibody, such as avelumab, durvalumab, atezolizumab, KN035, or CK-301.

[0249] In some embodiments, the immune checkpoint inhibitor is a (non-antibody) peptide inhibitor of PD-1 / PD-L1, such as AUNP12; a small molecule inhibitor of PD-L1, such as CA-170, or a macrocyclic peptide, such as BMS-986189.

[0250] In certain embodiments, an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) that specifically binds to IGSF8 ("IGSF8-binding antagonist"), e.g., an IGSF8 antagonist or antigen-binding fragment thereof, is administered together with a second immune checkpoint inhibitor (e.g., an inhibitor of the PD-1 or PD-L1 pathway) to a subject with a disease in which stimulation of the immune system is beneficial, e.g., cancer or an infectious disease. The two antagonists can be administered simultaneously or sequentially, e.g., as described below for the combination of an IGSF8 antagonist and an immuno-oncology agent. For the treatment of cancer or an infectious disease, treatment with the IGSF8-binding antagonist may be supplemented with one or more additional therapeutic agents, e.g., a checkpoint modulator. In some embodiments, the IGSF8 antagonist is an antibody or antigen-binding fragment thereof that specifically binds to D1 (Ig-V set domain) of IGSF8.

[0251] In certain embodiments, the KIR3DL1 / 2 antagonist specifically binds to KIR3DL1 / 2 ("antagonist that binds to KIR3DL1 / 2"), e.g., a KIR3DL1 / 2 antagonist antibody or antigen-binding fragment thereof is administered together with a second antagonist, e.g., an immune checkpoint inhibitor (e.g., an inhibitor of the PD-1 or PD-L1 pathway), to a subject with a disease in which stimulation of the immune system is expected to be beneficial, e.g., cancer or an infectious disease. The two antagonists may be administered simultaneously or sequentially, e.g., as described below with respect to the combination of a KIR3DL1 / 2 antagonist and an immuno-oncology agent. One or more additional therapeutic agents, e.g., a checkpoint modulator, may be added to treatment with a KIR3DL1 / 2-binding antagonist to treat cancer or an infectious disease. In some embodiments, the KIR3DL1 / 2 antagonist is an antibody or antigen-binding fragment thereof that specifically binds to D2 (middle Ig-like domain) of KIR3DL1 / 2, e.g., an antibody or antigen-binding fragment that binds to S165, I171, and / or M186 of KIR3DL1 / 2 or inhibits IGSF8 binding via S165, I171, and / or M186.

[0252] In certain embodiments, the KLRC1 / D1 antagonist specifically binds to KLRC1 / D1 ("antagonist that binds to KLRC1 / D1"), e.g., a KLRC1 / D1 antagonist antibody or antigen-binding fragment thereof is administered together with a second antagonist, e.g., an immune checkpoint inhibitor (e.g., an inhibitor of the PD-1 or PD-L1 pathway), to a subject with a disease in which immune system stimulation is expected to be beneficial, e.g., cancer or an infectious disease. The two antagonists may be administered simultaneously or sequentially, e.g., as described below with respect to the combination of a KLRC1 / D1 antagonist and an immuno-oncology agent. One or more additional therapeutic agents, e.g., a checkpoint modulator, may be added to treatment with a KLRC1 / D1-binding antagonist to treat cancer or an infectious disease.

[0253] In certain embodiments, the IGSF8 antagonist (e.g., the anti-IGSF8 monoclonal antibody or its antigen-binding fragment of the present invention) and / or the KIR3DL1 / 2 antagonist and / or the KLRC1 / D1 antagonist are administered to a subject, for example, a subject with cancer, either simultaneously or sequentially with another treatment. For example, the IGSF8 antagonist (e.g., the anti-IGSF8 monoclonal antibody or its antigen-binding fragment of the present invention) and / or the KIR3DL1 / 2 antagonist and / or the KLRC1 / D1 antagonist may be administered together with one or more of radiation therapy, surgery, or chemotherapy, for example, targeted chemotherapy or immunotherapy. Immunotherapies, for example, cancer immunotherapy, include cancer vaccines and immuno-oncology agents.

[0254] The IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or KIR3DL1 / 2 antagonist and / or KLRC1 / D1 antagonist can be, for example, a protein, antibody, antibody fragment, or small molecule that binds to IGSF8, KIR / 3DL1 / 2, or KLRC1 / D1, respectively. The IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or KIR3DL1 / 2 antagonist and / or KLRC1 / D1 antagonist can be an antibody or antigen-binding fragment thereof that specifically binds to IGSF8, KIR3DL1 / 2, or KLRC1 / D1, respectively.

[0255] In certain embodiments, a method for treating a subject with cancer comprises administering to the subject with cancer an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist, e.g., an IGSF8 antibody and / or a KIR3DL1 / 2 antibody and / or a KLRC1 / D1 antibody, and one or more immuno-oncology agents, e.g., an immune checkpoint inhibitor.

[0256] Immunotherapy, for example, therapy using immuno-oncology agents, is effective in enhancing, stimulating, and / or upregulating immune responses in subjects. In one embodiment, administering an IGSF8 antagonist (e.g., the anti-IGSF8 monoclonal antibody or its antigen-binding fragment of the present invention) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist together with an immuno-oncology agent (e.g., a PD-1 inhibitor) has a synergistic effect in treating cancer, for example, in inhibiting tumor growth.

[0257] In one embodiment, the IGSF8 antagonist (e.g., the anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or the KIR3DL1 / 2 antagonist and / or the KLRC1 / D1 antagonist are administered sequentially before the administration of the immuno-oncology agent. In one embodiment, the IGSF8 antagonist (e.g., the anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or the KIR3DL1 / 2 antagonist and / or the KLRC1 / D1 antagonist are administered simultaneously with the immuno-oncology agent (e.g., a PD-1 inhibitor). In a further embodiment, the IGSF8 antagonist (e.g., the anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or the KIR3DL1 / 2 antagonist and / or the KLRC1 / D1 antagonist are administered sequentially after the administration of the immuno-oncology agent (e.g., a PD-1 inhibitor).

[0258] Administration of the two agents may begin, for example, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 3 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 3 days, 5 days, 7 days, or one or more weeks apart, or administration of the second agent may begin, for example, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 3 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 3 days, 5 days, 7 days, or one or more weeks after administration of the first agent.

[0259] In certain embodiments, the IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or KIR3DL1 / 2 antagonist and / or KLRC1 / D1 antagonist and the immuno-oncology agent (e.g., a PD-1 inhibitor) are administered to the patient simultaneously, e.g., by simultaneous infusion, e.g., over a period of 30 or 60 minutes. The IGSF8 antagonist may be co-formulated with the immuno-oncology agent (e.g., a PD-1 inhibitor).

[0260] Immuno-oncology agents include, for example, small molecule drugs, antibodies or fragments thereof, or other biological or small molecules. Examples of biological immuno-oncology agents include, but are not limited to, antibodies, antibody fragments, vaccines, and cytokines. In one embodiment, the antibody is a monoclonal antibody. In certain embodiments, the monoclonal antibody is a humanized antibody or a human antibody.

[0261] In one embodiment, the immuno-oncology agent is an agonist of (i) a stimulatory (including costimulatory) molecule (e.g., a receptor or ligand) or an antagonist of (ii) an inhibitory (including co-inhibitory) molecule (e.g., a receptor or ligand) on an immune cell, e.g., a T cell, both of which result in the amplification of an antigen-specific T cell response. In a particular embodiment, the immuno-oncology agent is an agonist of (i) a stimulatory (including costimulatory) molecule (e.g., a receptor or ligand) or an antagonist of (ii) an inhibitory (including co-inhibitory) molecule (e.g., a receptor or ligand) on a cell involved in innate immunity, wherein the immuno-oncology agent enhances innate immunity. Such immuno-oncology agents are often referred to as immune checkpoint modulators, e.g., immune checkpoint inhibitors or immune checkpoint stimulators.

[0262] In certain embodiments, the immuno-oncology agent targets a stimulating or inhibitory molecule that is a member of the immunoglobulin superfamily (IgSF). For example, the immuno-oncology agent targets (or specifically binds to) a member of the B7 family of membrane-bound ligands or a costimulatory or co-inhibitory receptor that specifically binds to a B7 family member, including B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 and B7-H6. The immuno-oncology agent can be an agent that targets a member of the TNF family of membrane-bound ligands or a costimulatory or co-inhibitory receptor that specifically binds to a TNF family of membrane-bound ligands. Exemplary TNF and TNFR family members that may be targeted by immuno-oncology agents include CD40 and CD40L, OX-40, OX-40L, GITR, GITRL, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTfiR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin alpha / TNβ, TNFR2, TNFα, LTfiR, lymphotoxin a 1β2, FAS, FASL, RELT, DR6, TROY and NGFR. The immuno-oncology agent that can be used in combination with IGSF8 antagonist to treat cancer is, for example, an antibody that targets IgSF members, such as B7 family members, B7 receptor family members, TNF family members or TNFR family members, for example.

[0263] In one embodiment, the IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or KIR3DL1 / 2 antagonist and / or KLRC1 / D1 antagonist is (i) an antagonist of a protein that inhibits T cell activation (e.g., an immune checkpoint inhibitor), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM3, galectin-9, CEACAM-1, BTLA, CD69, galectin-1, TIGIT, and (ii) an agonist of a protein that stimulates T cell activation, such as one or more of B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, CD40L, DR3, and CD28H.

[0264] In one embodiment, the immuno-oncology agent is an agent that inhibits (i.e., an antagonist of) cytokines that inhibit T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines) or is an agonist (e.g., the cytokines themselves) of cytokines that stimulate T cell activation and stimulate immune responses, such as IL-2, IL-7, IL-12, IL-15, IL-21, and IFNα.

[0265] Other agents that can be combined with IGSF8 antagonists (e.g., the anti-IGSF8 monoclonal antibody or its antigen-binding fragment of the present invention) and / or KIR3DL1 / 2 antagonists and / or KLRC1 / D1 antagonists to stimulate the immune system, for example, for the treatment of cancer and infectious diseases, include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, anti-IGSF8 antagonists (e.g., the anti-IGSF8 monoclonal antibody or its antigen-binding fragment of the present invention) can be combined with KIR antagonists, such as KIR3DL1 / 2 antagonists and / or antagonists against KLRC1 / D1.

[0266] Still other agents for combination therapy include agents that inhibit or deplete macrophages or monocytes, non-limiting examples of which include CSF-IR antagonists, such as CSF-IR antagonist antibodies, for example RG7155 (WO 1 / 70024, WO 11 / 107553, WO 11 / 131407, WO 13 / 87699, WO 13 / 119716, WO 13 / 132044) or FPA008 (WO 11 / 140249, WO 13169264, WO 14 / 036357).

[0267] Immuno-oncology agents also include agents that inhibit TGF-β signaling.

[0268] Additional agents that may be combined with the IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or KIR3DL1 / 2 antagonist and / or KLRC1 / D1 antagonist include agents that enhance tumor antigen presentation, such as dendritic cell vaccines, cellular vaccines that secrete GM-CSF, CpG oligonucleotides, and imiquimod, or therapeutic agents that enhance the immunogenicity of tumor cells (e.g., anthracyclines).

[0269] Still other therapies that may be combined with IGSF8 antagonists (e.g., anti-IGSF8 monoclonal antibodies or antigen-binding fragments thereof of the present invention) and / or KIR3DL1 / 2 antagonists and / or KLRC1 / D1 antagonists include therapeutic agents that deplete or block Treg cells, for example, agents that specifically bind to CD25.

[0270] Another therapy that may be combined with an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist is a therapeutic agent that inhibits metabolic enzymes such as indoleamine dioxygenase (IDO), dioxygenase, arginase, or nitric oxide synthase.

[0271] Other classes of agents that may be used include agents that inhibit the formation of adenosine or that inhibit the adenosine A2A receptor.

[0272] Other therapies that may be combined with IGSF8 antagonists and / or KIR3DL1 / 2 antagonists and / or KLRC1 / D1 antagonists to treat cancer include therapies that reverse / prevent T cell anergy or exhaustion, and therapies that cause innate immune activation and / or inflammation at the tumor site.

[0273] The IGSF8 antagonists (e.g., anti-IGSF8 monoclonal antibodies or antigen-binding fragments thereof of the present invention) and / or KIR3DL1 / 2 antagonists and / or KLRC1 / D1 antagonists may be combined with each other and / or with more than one immuno-oncology agent (e.g., immune checkpoint inhibitors), or may be combined in a combinatorial approach that targets multiple elements of the immune pathway, such as one or more of the following: therapeutic agents that enhance tumor antigen presentation (e.g., dendritic cell vaccines, cellular vaccines that secrete GM-CSF, CpG oligonucleotide vaccines, and the like). imiquimod); therapies that inhibit negative immune regulation, for example, by inhibiting the CTLA-4 and / or PD1 / PD-L1 / PD-L2 pathways and / or by depleting or blocking Tregs or other immunosuppressive cells; therapeutic agents that stimulate positive immune regulation, for example, therapeutic agents that stimulate the CD-137, OX-40 and / or GITR pathways and / or in combination with agonists that stimulate T cell effector function; therapeutic agents that systemically increase the frequency of anti-tumor T cells; for example, using antagonists of CD25 (e.g., daclizumab) or ex Therapeutic agents that deplete or inhibit Tregs, e.g., Tregs in tumors, by in vivo depletion with anti-CD25 beads; therapeutic agents that affect the function of suppressor myeloid cells in tumors; therapeutic agents that enhance the immunogenicity of tumor cells (e.g., anthracyclines); adoptive T cell or NK cell transfer, such as genetically modified cells, e.g., cells modified with chimeric antigen receptors (CAR-T therapy); therapies that inhibit metabolic enzymes such as indoleamine dioxygenase (IDO), dioxygenase, arginase, or nitric oxide synthase; therapeutic agents that reverse / prevent T cell anergy or exhaustion; therapeutic agents that cause innate immune activation and / or inflammation at the tumor site; administration of immunostimulatory cytokines or blocking immunosuppressive cytokines.

[0274] For example, the IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or KIR3DL1 / 2 antagonist and / or KLRC1 / D1 antagonist can be used in conjunction with one or more agonist agents that ligate positive costimulatory receptors; one or more antagonists (blocking agents) that attenuate signaling through inhibitory receptors, such as antagonists that overcome distinct immunosuppressive pathways within the tumor microenvironment (e.g., antagonists that block PD-L1 / PD-1 / PD-L2 interactions); one or more agents that systemically increase the frequency of anti-tumor immune cells, e.g., T cells, or that deplete or inhibit Tregs (e.g., by inhibiting CD25); one or more agents that inhibit metabolic enzymes such as IDO; one or more agents that reverse / prevent T cell anergy or depletion; and one or more agents that cause innate immune activation and / or inflammation at the tumor site.

[0275] In one embodiment, a subject with a disease that may benefit from immune system stimulation, such as cancer or an infectious disease, is treated by administering to the subject an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist and an immuno-oncology agent, wherein the immuno-oncology agent is a CTLA-4 antagonist, e.g., an antagonist CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab.

[0276] In one embodiment, a subject with a disease that may benefit from immune system stimulation, such as cancer or an infectious disease, is treated by administering to the subject an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist, and an immuno-oncology agent, wherein the immuno-oncology agent is a PD-1 antagonist, e.g., an antagonist PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012 / 145493). The immuno-oncology agent may also include pidilizumab (CT-011). Another approach to targeting the PD-1 receptor is a combination protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, which is termed AMP-224.

[0277] In one embodiment, a subject with a disease that may benefit from immune system stimulation, such as cancer or an infectious disease, is treated by administering to the subject an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist, and an immuno-oncology agent, where the immuno-oncology agent is a PD-L1 antagonist, e.g., an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include, for example, MPDL3280A (RG7446; WO 2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO 2007 / 005874), MSB0010718C (WO 2013 / 79174), or rHigM12B7.

[0278] In one embodiment, a subject with a disease that may benefit from immune system stimulation, such as cancer or an infectious disease, is treated by administering to the subject an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or its antigen-binding fragment of the present invention) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist, and an immuno-oncology agent, wherein the immuno-oncology agent is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody. Suitable LAG3 antibodies include, for example, BMS-986016 (WO 10 / 19570, WO 14 / 08218), or IMP-731 or IMP-321 (WO 8 / 132601, WO 9 / 44273).

[0279] In one embodiment, a subject suffering from a disease that can benefit from immune system stimulation, such as cancer or an infectious disease, is treated by administering to the subject an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or its antigen-binding fragment of the present invention) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist, and an immuno-oncology agent, wherein the immuno-oncology agent is a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab or PF-05082566 (WO 12 / 32433).

[0280] In one embodiment, a subject suffering from a disease that can benefit from immune system stimulation, such as cancer or an infectious disease, is treated by administering to the subject an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or its antigen-binding fragment of the present invention) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist, and an immuno-oncology agent, wherein the immuno-oncology agent is a GITR agonist, such as an agonistic GITR antibody. Suitable GITR antibodies include, for example, TRX-518 (WO 06 / 105021, WO 09 / 009116), MK-4166 (WO 11 / 028683), or the GITR antibodies disclosed in WO 2015 / 031667.

[0281] In one embodiment, a subject with a disease that may benefit from immune system stimulation, such as cancer or an infectious disease, is treated by administering to the subject an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist, and an immuno-oncology agent, wherein the immuno-oncology agent is an OX40 agonist, such as an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383, MEDI-6469, or MOXR0916 (RG7888; WO 06 / 029879).

[0282] In one embodiment, a subject with a disease that can benefit from immune system stimulation, such as cancer or an infectious disease, is treated by administering to the subject an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist, and an immuno-oncology agent, wherein the immuno-oncology agent is a CD40 agonist, e.g., an agonistic CD40 antibody. In a specific embodiment, the immuno-oncology agent is a CD40 antagonist, e.g., an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab (HCD122), dacetuzumab (SGN-40), CP-870,893, or Tyrob7 / 4.

[0283] In one embodiment, a subject with a disease that may benefit from immune system stimulation, such as cancer or an infectious disease, is treated by administering to the subject an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist, and an immuno-oncology agent, wherein the immuno-oncology agent is a CD27 agonist, e.g., an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, valilumab (CDX-1127).

[0284] In one embodiment, a subject having a disease that may benefit from stimulation of the immune system, such as cancer or an infectious disease, is treated by administering to the subject an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist, and an immuno-oncology agent, wherein the immuno-oncology agent is MGA271(-B7H3) (WO 11 / 109400).

[0285] In one embodiment, a subject having a disease that may benefit from stimulation of the immune system, such as cancer or an infectious disease, is treated by administering to the subject an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist, and an immuno-oncology agent, wherein the immuno-oncology agent is a KIR antagonist, e.g., lirilumab.

[0286] In one embodiment, a subject having a disease that may benefit from stimulation of the immune system, such as cancer or an infectious disease, is treated by administering to the subject an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist, and an immuno-oncology agent, wherein the immuno-oncology agent is an IDO antagonist. Suitable IDO antagonists include, for example, INCB-024360 (WO 2006 / 122150, WO 07 / 75598, WO 08 / 36653, WO 08 / 36642), indoximod, NLG-919 (WO 9 / 73620, WO 9 / 1156652, WO 11 / 56652, WO 12 / 142237) or F001287.

[0287] In one embodiment, a subject having a disease that may benefit from stimulation of the immune system, such as cancer or an infectious disease, is treated by administering to the subject an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist, and an immuno-oncology agent, wherein the immuno-oncology agent is a Toll-like receptor agonist, such as a TLR2 / 4 agonist (e.g., Bacillus Calmette-Guerin), a TLR7 agonist (e.g., Hiltonol or Imiquimod), a TLR7 / 8 agonist (e.g., Resiquimod), or a TLR9 agonist (e.g., CpG7909).

[0288] In one embodiment, a subject having a disease that may benefit from stimulation of the immune system, such as cancer or an infectious disease, is treated by administering to the subject an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist, and an immuno-oncology agent, wherein the immuno-oncology agent is a TGF-β inhibitor, e.g., GC1008, LY2157299, TEW7197 or IMC-TR1.

[0289] Another therapy that may be combined with an IGSF8 antagonist (e.g., an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof of the present invention) and / or a KIR3DL1 / 2 antagonist and / or a KLRC1 / D1 antagonist is a therapeutic antibody, e.g., a therapeutic antibody effective in treating cancer. Exemplary, but non-limiting, therapeutic antibodies include 3F8, 8H9, abagovomab, abciximab, abirulumab, abrezekimab, abrilumab, actoxumab, adalimumab, adecatumumab, aducanumab, afacevicumab, afelimomab, alacizumab pegol, alemtuzumab, alirocumab, altumomab pentetate, amatuximab, amivantamab, anatumomab mafenatox, andecaliximab, anetumab ravtansine, anifrolumab, and Rukinzumab, apolizumab, aprtumab ixadotin, arcitumomab, asclinbacumab, acelizumab, atezolizumab, atidortoxumab, atinumab, atorolimumab, avelumab, azintuximab vedotin, bapineuzumab, basiliximab, bavituximab, BCD-100, bectumomab, begelomab, belantamab mafodotin, belimumab, bemarituzumab, benralizumab, berlimatoxumab, bermekimab, bersanlimab, bertilimumab , besilesomab, bevacizumab, bezlotoxumab, biciromab, bimagrumab, bimekizumab, viltamimab, bivatuzumab, bleselumab, blinatumomab, brontuximab, brosozumab, bococizumab, brazikumab, brentuximab vedotin, briakinumab, brodalumab, brolucizumab, brontiximab, burosumab, cabilalizumab, camidalumab tesirin, camrelizumab, canakinumab, cantuzumab mertansine, cantuzumab mertansine , caplacizumab, capromab, carlumab, carotuximab, catumaxomab, cBR-doxorubicin immunoconjugate, cedelizumab, cemiplimab, sergituzumab amnaleukin, certolizumab pegol, cetrelimab, cetuximab, civisatamab, cirumtuzumab, sitatuzumab bogatox, cixutumumab, clazakizumab, clenoliximab, clivatuzumab tetraxetan, codrituzumab, cofetuzumab peridotin, coltuximab tetraxetan,Conatumumab, concizumab, cosfrobiximab, crenezumab, crizanlizumab, clotedumab, CR6261, cusatuzumab, dacetuzumab, daclizumab, darotuzumab, dapirolizumab pegol, daratumumab, dectrecumab, demcizumab, denintuzumab mafodotin, denosumab, depatuxizumab mafodotin, delrotuximab biotin, detumomab, dezamizumab, dinutuximab, zilidabumab, domaglotuzumab, dorlimomab alitoxin, dostarlimab, drozitumab, DS-8201, durigotuzumab, dupilumab, de Urvalumab, dusigitumab, duvortuxizumab, ecromeximab, eculizumab, edovacomab, edrecolomab, efalizumab, efangumab, eldelumab, elezanumab, elgemtuzumab, elotuzumab, elsilimomab, emactuzumab, emapalumab, emibetuzumab, emicizumab, enapotamab vedotin, enavatuzumab, enfortumab vedotin, enlimomab pegol, enoblitzumab, enokizumab, enoticumab, ensituximab, epitumomab cituxetan, epratuzumab, eptinezumab, erenumab, er Lizumab, ertumaxomab, etaracizumab, etigilimab, etorolizumab, evinacumab, evolocumab, exbivirumab, fanolesomab, faralimomab, faricimab, farletuzumab, fasinumab, FBTA05, felvizumab, fezakinumab, fivatuzumab, ficlatuzumab, figitumumab, filibumab, framvotumab, fretikumab, flotetuzumab, fontolizumab, foralumab, foravirumab, fremanezumab, fresolimumab, flobocimab, furnevetomab, furanumab, futuximab, galcane Ibuprofen, galiximab, gancotamab, ganitumab, gantenerumab, gatipotuzumab, gavilimomab, gezivumab, gemtuzumab ozogamicin, gevokizumab, zirvetumab, dimcirumab, dilentuximab, glenbatumumab vedotin, golimumab, gomiliximab, goslanemab, guselkumab, ranalumab, ibalizumab, IBI308, ibritumomab tiuxetan, icrucumab, idarucizumab, ifavotuzumab, igovomab, iradatuzumab vedotin, IMAB363, imalumab, imaprelimab, imciromab, imgatuzumabInclacumab, indatuximab ravtansine, indusatumab vedotin, inebilizumab, infliximab, intetumumab, inolimomab, inotuzumab ozogamicin, ipilimumab, Iomab-B, iratumumab, isatuximab, iscalimab, istiratumab, itolizumab, ixekizumab, keliximab, labetuzumab, lacunotuzumab, radiratuzumab vedotin, lampalizumab, lanadelumab, landgrozumab, laprituximab emtansine, ralcabiximab, lebrikizumab, remaresomab, lendalizumab, lenbet Rubimab, lenzilumab, lerdelimumab, leronlimab, lesofabumab, letolizumab, lexatumumab, ribivirumab, rifastuzumab vedotin, ligelizumab, loncastuximab tesirin, rosatuximab vedotin, rilotumab satetraxetan, lintuzumab, lirilumab, roderucizumab, loxivetumab, lorvotuzumab mertansine, lucatumumab, lurizumab pegol, rumiliximab, lumletuzumab, rupartumab, rupartumab amadotin, rutikizumab, mapatumumab, marjetuximab, marstacimab, maslimomab, Mavrilimumab, matuzumab, mepolizumab, metelimumab, milatuzumab, minletumomab, mirikizumab, mirvetuximab soravtansine, mitumomab, modotuximab, mogamulizumab, monalizumab, morolimumab, mosunetuzumab, motavizumab, moxetumomab pasudotox, muromonab-CD3, nacolomabutafenatox, namilumab, naptumomab estafenatox, naratuximab emtansine, narutumab, natalizumab, nabicixizumab, naxitamab, nebacumab, necitumumab, nemolizumab, NEOD 001, nerelimomab, nesbacumab, netakimab, nimotuzumab, nirsevimab, nivolumab, nofetumomab merpentan, obilutoxaximab, obinutuzumab, ocralatuzumab, ocrelizumab, odulimomab, ofatumumab, olaratumab, oleculumab, orendalizumab, olokizumab, omalizumab, omburtamab, OMS721, onartuzumab, ontuxizumab, ombatilimab, opicinumab, oportuzumab monatox, oregovomab, olticumab, otelixizumab, otilimab, otlertuzumab, oxelumab,Ozanezumab, ozoralizumab, pasivaximab, palivizumab, pamrevlumab, panitumumab, pancomab, panobacumab, palsatuzumab, pascolizumab, pasotuximab, pateclizumab, patritumab, PDR001, pembrolizumab, pemtumomab, perakizumab, pertuzumab, pexelizumab, pidilizumab, pinatuzumab vedotin, pintumomab, placurumab, prezalumab, prozalizumab, pogalizumab, polatuzumab vedotin, ponezumab, polgabiximab, prasinezumab, prezalizumab, priliximab, prozalizumab Ritoxaximab, Pritumumab, PRO140, Kirizumab, Racotumomab, Radolezumab, Rafivirumab, Ralpancizumab, Ramucirumab, Ranevetomab, Ranibizumab, Raxibacumab, Ravagalimab, Ravtolimab, Refanezumab, Regavirumab, REGN-EB, Lelatolimab, Lemtolumab, Reslizumab, Rilotumumab, Linucumab, Risankizumab, Rituximab, Rivabuzumab pegol, Lobatumumab, Rmab, Lorezumab, Romilkimab, Romosozumab, Rontalizumab, Rosmantuzumab, Rovalituzumab Tecilline ... Ibuprofen, rozanolixizumab, ruplizumab, SA237, sacituzumab govitecan, samalizumab, samrotamab vedotin, sarilumab, satralizumab, satumomab pendetide, secukinumab, selicrelumab, seribantumab, cetoxaximab, setursumab, sevirumab, sibrotuzumab, SGN-CD19A, SHP647, sifalimumab, siltuximab, simtuzumab, siplizumab, siltratumab vedotin, sirukumab, sofituzumab vedotin, solanezumab, solitomab, sonepcizumab, sontuzumab, spartalizumab, Stamulumab, sulesomab, sputumab, stimulimab, subizumab, subratoxumab, tabalumab, tacatuzumab tetraxetan, tadocizumab, talacuzumab, talizumab, talquetamab, tamtubetomab, tanezumab, taplitumomab paptox, talexuzumab, tabolitumomab, tecristamab, tefibazumab, terimomab alitox, telisotuzumab, telisotuzumab vedotin, tenatumomab, teneliximab, teplizumab, tepositamab, teprotumumab, tesidolumab, tetulomab, tezepelumab, TGN1412, tiburizumab,Tildrakizumab, tigatuzumab, timigtuzumab, timolumab, tiragolumab, tiragotumab, tislelizumab, tisotumab vedotin, TNX-650, tocilizumab, tomzotuximab, toralizumab, tosatoxumab, tositumomab, tobetumab, tralokinumab, trastuzumab, trastuzumab duocarmazine, trastuzumab emtansine, TRBS07, tregalizumab, tremelimumab, trevoglumab, tucotuzumab celmoleukin, tuvilumab, ublituximab, urocuplumab, urelumab, urtoxazumab, ustekinumab, utomilumab, vadastuximab butarili , vanalimab, bundeltuzumab vedotin, vanticutumab, vanucizumab, bapaliximab, valisacumab, varlilumab, batelizumab, vedolizumab, veltuzumab, bepalimomab, besencumab, visilizumab, bovalilizumab, volociximab, bonlerolizumab, bopratelimab, borsetuzumab mafodotin, votumumab, bunakizumab, xentuzumab, XMAB-5574, zalutumumab, zanolimumab, zatuximab, xenoctuzumab, diralimumab, zolbetuximab, (=IMAB362, claudiximab), zolimomab alitox, or a combination thereof.

[0290] 6. Exemplary IGSF8 Antagonists In some embodiments, the IGSF8 antagonist is an IGSF8 antibody. In some embodiments, the IGSF8 antagonist for treating cancer may be a non-antibody protein, such as soluble IGSF8 or a portion thereof (e.g., ECD) that inhibits the interaction between IGSF8 and its ligand, and optionally further includes a fusion partner in the form of a fusion molecule.

[0291] In some embodiments, the IGSF8 antagonist is a soluble ECD of KIR3DL1 / 2, such as the D2 domain of KIR3DL1 / 2, or a fragment thereof, that binds to IGSF8, and optionally may further comprise a fusion partner, such as a sequence tag (e.g., a His tag, a FLAG tag, etc.). Such an IGSF8 antagonist can bind to IGSF8 and block its binding to the KIR3DL1 / 2 receptor on NK cells, and thus block IGSF8-mediated down-regulation of NK cell activity and / or viability.

[0292] In some embodiments, the IGSF8 antagonist is a soluble ECD of KLRC1 / D1, such as the ECD of KLRC1 or KLRD1, or a fragment thereof, that binds to IGSF8, and optionally may further comprise a fusion partner, such as a sequence tag (e.g., a His tag, a FLAG tag, etc.). Such an IGSF8 antagonist can bind to IGSF8 and block its binding to the KLRC1 / D1 receptor on NK cells, and thus block IGSF8-mediated down-regulation of NK cell activity and / or viability.

[0293] In other embodiments, the antagonist may also be a small molecule or a small peptide.

[0294] IGSF8 antibody One aspect of the present invention provides a monoclonal antibody specific for IGSF8. In certain embodiments, the monoclonal antibody is specific for the extracellular domain (ECD) of IGSF8. In certain embodiments, the monoclonal antibody is specific for the Ig-V set extracellular domain (D1 domain) of IGSF8. In some embodiments, an antibody that blocks the binding of IGSF8 to its ligand is provided. In certain embodiments, the monoclonal antibody inhibits the binding of IGSF8 to KIR3DL2 and / or KIR3DL1, e.g., inhibits the binding of IGSF8 to residues S165, I171, and / or M186. In certain embodiments, the monoclonal antibody inhibits the binding of IGSF8 to KLRC1 / D1. In certain embodiments, the monoclonal antibody is cross-species reactive, e.g., the monoclonal antibody binds to both human and mouse IGSF8. In certain embodiments, the monoclonal antibody is specific for human IGSF8. In some embodiments, the IGSF8 antibody inhibits IGSF8-mediated signal transduction. In certain embodiments, the monoclonal antibody competes with any one of the anti-IGSF8 antibodies disclosed herein for binding to IGSF8. In certain embodiments, the monoclonal antibody binds to the same epitope on IGSF8 as any one of the anti-IGSF8 antibodies disclosed herein.

[0295] In some embodiments, the IGSF8 antibodies of the invention have a mAb concentration of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., 10 -8 M or less, e.g., 10 -8 M~10 -13 M, e.g., 10 -9 M~10 -13 Dissociation constant (K dIn certain embodiments, the IGSF8 antibody has a dissociation constant (Kd) for IGSF8, e.g., for human IGSF8, of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., ≦10 -8 M or less, e.g. 10 -8 M~10 -13 M, e.g., 10 -9 M~10 -13 M).

[0296] In some embodiments, an IGSF8 antibody having any of the characteristics provided herein inhibits IGSF8 signaling, e.g., signaling via KIR3DL1 / 2 and / or KLRC1 / D1, by at least 25%, 50%, 75%, 80%, 90%, or 100%. For example, KIR3DL1 / 2 and / or KLRC1 / D1 signaling can be assayed in NK cells based on IFNγ secretion upon binding to IGSF8, and such secretion can be analyzed using standard techniques such as ELISA. In some embodiments, the IGSF8 antibody inhibits signaling in NK cells, e.g., in any one of the signaling pathways described in Figure 2D (e.g., cell cycle, DNA replication, etc.) or Figure 2E (e.g., PRF1, GZMB, or GZMA).

[0297] In some embodiments, IGSF8 antibodies of the invention include antibodies described herein, such as C1 to C39, or C30 to C39, described in Example 7, as well as any one of antibodies L1-01 to L1-033, and L2-01 to L2-010, described in Example 24 (all of which are incorporated by reference herein), as well as any of the antibodies described in this section.

[0298] Unless explicitly stated, all antibody and CDR sequences are based on the IMGT numbering scheme, except for C1-C29, which are annotated using the Kabat numbering scheme (while others, such as C30-C39 and those based on L1 / L2 derivatives, are based on the IMGT numbering scheme). In addition, the heavy chain-only sequence consensus / motif after C39, as well as the CDR sequences (L1 / L2 derivatives) in the CDR region mutation analysis, are also based on the IMGT numbering scheme.

[0299] Using the HCVR CDR1-3 sequences of the high-affinity anti-IGSF8 antibodies C30-C39 as query sequences, numerous similar CDR sequences were identified in a patented human antibody library, and antibodies with such small CDR variations are also anti-IGSF8 antibodies of the present invention that are specific to IGSF8 (e.g., specific to the Ig-V set domain or the D1 domain of the ECD of IGSF8).

[0300] Similarly, using the LCVR CDR1-3 sequences of the high-affinity anti-IGSF8 antibodies C30-C39 as query sequences, numerous similar CDR sequences were identified in a patented human antibody library, and antibodies with such small CDR variations are also anti-IGSF8 antibodies of the present invention specific to IGSF8 (e.g., specific to the Ig-V set domain or the D1 domain of the ECD of IGSF8).

[0301] Thus, in some embodiments, the anti-IGSF8 antibody of the present invention comprises a monoclonal antibody or antigen-binding portion / fragment thereof specific for IGSF8 (e.g., specific for the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises: (a) a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 469, 470, and 471, respectively, which are similar to and include HCVR CDR1-3 of monoclonal antibody C30 / B34; and / or (b) a light chain variable region (LCVR) comprising LCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 562, 563, and 564, respectively, which are similar to and include LCVR CDR1-3 of monoclonal antibody C30 / B34. SEQ ID NO: 469: G Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 A, wherein Xaa1 = F or Y; Xaa2 = S or T; Xaa3 = L, F or I; Xaa4 = R, S or I; Xaa5 = D or S; and Xaa6 = Y or S. SEQ ID NO: 470: I Xaa1 GSGG Xaa2 T, wherein Xaa1 = S or T, and Xaa2 = N or S. SEQ ID NO: 471: Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8, wherein Xaa1 = E, A or S, Xaa2 = R, L or S, Xaa3 = W, A, Y, V, G or S, Xaa4 = R, L or S, Xaa5 = L, Y, P, T, I, N, K, H or Q, Xaa6 = L, V, F, I, G, R or H, Xaa7 = A, Y, V or any acidic residue (D / E), and Xaa8 = Y, A, T, P, K, S or Q. SEQ ID NO: 562: Xaa1 Xaa2 Xaa3 H Xaa4 Y, wherein Xaa1 = K, Q, P or H, Xaa2 = S, V, I or R, Xaa3 = N, S, L, I or M, Xaa4 = K, N or T, SEQ ID NO: 563: AAS, and Sequence number 564: Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 P Xaa7 Xaa8, wherein Xaa1 = L, Q, K or H, Xaa2 = L, Q, K or H, Xaa3 = S, I or R, Xaa4 = Y or F, Xaa5 = P, N, S or T, Xaa6 = P, N, S or T, Xaa7 = L, I or R, Xaa8 = P, N, S or T.

[0302] In some embodiments, the anti-IGSF8 antibody of the present invention comprises a monoclonal antibody or antigen-binding portion / fragment thereof specific for IGSF8 (e.g., specific for the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises: (a) a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 472, 473, and 474, respectively, which are similar to and include HCVR CDR1-3 of monoclonal antibody C31 / B46; and / or (b) a light chain variable region (LCVR) comprising LCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 565, 566, and 567, respectively, which are LCVR CDR1-3 of monoclonal antibody C31 / B46. SEQ ID NO: 472: GFTFSTYG, SEQ ID NO: 473: IWDDGSYK, and Sequence number 474: A Xaa1 GYS Xaa2 S Xaa3 Xaa4 A Xaa5, wherein Xaa1 = V or G, Xaa2 = D or Y, Xaa3 = Y, D or S, Xaa4 = R, L or M, and Xaa5 = L, I or S. SEQ ID NO: 565: QGISTF, SEQ ID NO: 566: AAS, and SEQ ID NO:567: QQTYSTQWT.

[0303] In some embodiments, the anti-IGSF8 antibodies of the present invention comprise a monoclonal antibody or antigen-binding portion / fragment thereof specific for IGSF8 (e.g., specific for the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises: (a) a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 475, 476, and 477, respectively, which are similar to and include HCVR CDR1-3 of monoclonal antibody C32 / B104; and / or (b) a light chain variable region (LCVR) comprising LCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 568, 569, and 570, respectively, which are LCVR CDR1-3 of monoclonal antibody C32 / B104. SEQ ID NO: 475: GYTFTNDI, SEQ ID NO: 476: INAGYGNT, and SEQ ID NO: 477: ARGYYRSPTW Xaa1 D Xaa2, where Xaa1 = F or I, and Xaa2 = W or Y. SEQ ID NO: 568: QSISSW, SEQ ID NO: 569: KAS, and Sequence number 570: QQYGDYPYT.

[0304] In some embodiments, the anti-IGSF8 antibody of the present invention comprises a monoclonal antibody or antigen-binding portion / fragment thereof specific for IGSF8 (e.g., specific for the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises: (a) a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 478, 479, and 480, respectively, which are similar to and include HCVR CDR1-3 of monoclonal antibody C33 / 1C2; and / or (b) a light chain variable region (LCVR) comprising LCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 571, 572, and 573, respectively, which are LCVR CDR1-3 of monoclonal antibody C33 / 1C2. SEQ ID NO: 478: GFTFSTYG, SEQ ID NO: 479: IWDDGSYK, and SEQ ID NO: 480: ARD Xaa1 S Xaa2 W Xaa3 YAFD Xaa4, wherein Xaa1 = G or C, Xaa2 = V or G, Xaa3 = V or G, and Xaa4 = L or I. SEQ ID NO: 571: Xaa1 D Xaa2 Xaa3 Xaa4 Y, wherein Xaa1 = K, Q, P or H, Xaa2 = S, N, I or L, Xaa3 = S, I or R, Xaa4 = any acidic residue (D / E). SEQ ID NO: 572: DAA, and SEQ ID NO: 573: Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9, wherein Xaa1 = L, Q, K or H, Xaa2 = Q, K, H or L, Xaa3 = Y, S, D or F, Xaa4 = V, A or any acidic residue (D / E), Xaa5 = S, I or R, Xaa6 = L, F or V, Xaa7 = H, P or T, Xaa8 = Y, S, F or D, Xaa9 = P, N, S or T.

[0305] In some embodiments, the anti-IGSF8 antibody of the present invention comprises a monoclonal antibody or antigen-binding portion / fragment thereof specific for IGSF8 (e.g., specific for the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises: (a) a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 481, 482, and 483, respectively, which are similar to and include HCVR CDR1-3 of monoclonal antibody C34 / 1D7; and / or (b) a light chain variable region (LCVR) comprising LCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 574, 575, and 576, respectively, which are similar to and include LCVR CDR1-3 of monoclonal antibody C34 / 1D7. SEQ ID NO: 481: GFT Xaa1 Xaa2 S Xaa3 A, wherein Xaa1 = V or F, Xaa2 = N or S, and Xaa3 = F or Y; SEQ ID NO: 482: I Xaa1 GSGG Xaa2 T, wherein Xaa1 = S or T, and Xaa2 = S or G, and SEQ ID NO: 483: AR Xaa1 V Xaa2 GYGAF Xaa3 Xaa4, where Xaa1 = any acidic residue (D / E), Xaa2 = any acidic residue (D / E), Xaa3 = A or any acidic residue (D / E), and Xaa4 = L or I. SEQ ID NO: 574: Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Y, wherein Xaa1 = Q, P or any basic residue (R / H / K), Xaa2 = S, N or T, Xaa3 = N, S, L, I or M, Xaa4 = H, R, I or S, Xaa5 = H, N, D, S, K, T or I, SEQ ID NO: 575: GAS, and SEQ ID NO: 576: Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9, wherein Xaa1 = H, Q, K, L or P, Xaa2 = H, E, Q, K, L or P, Xaa3 = N, A, S, T or P, Xaa4 = Y, S, V, L or F, Xaa5 = S, I or R, Xaa6 = V, A or any acidic residue (D / E), Xaa7 = A, Q, K, R, T or P, Xaa8 = Y or F, Xaa9 = P, N, S or T.

[0306] In some embodiments, the anti-IGSF8 antibody of the present invention comprises a monoclonal antibody or antigen-binding portion / fragment thereof specific for IGSF8 (e.g., specific for the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises: (a) a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 484, 485, and 486, respectively, which are similar to and include HCVR CDR1-3 of monoclonal antibody C35 / 1B1; and / or (b) a light chain variable region (LCVR) comprising LCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 577, 578, and 579, respectively, which are LCVR CDR1-3 of monoclonal antibody C35 / 1B1. SEQ ID NO: 484: GFTF Xaa1 Xaa2 Xaa3 A, where Xaa1 = R, N or S, Xaa2 = D or S, and Xaa3 = F or Y; SEQ ID NO: 485: I Xaa1 GSGG Xaa2 T, wherein Xaa1 = S or T, and Xaa2 = N, S, or G; SEQ ID NO: 486: A Xaa1 Xaa2 GWE Xaa3 RTPG Xaa4 Xaa5 D Xaa6, wherein Xaa1 = R or S, Xaa2 = V or any acidic residue (D / E), Xaa3 = V or G, Xaa4 = D or Y, Xaa5 = L, F or I, and Xaa6 = D, Y, H or S. SEQ ID NO: 577: HRIFSY, SEQ ID NO: 578: GAS, and Sequence number 579: QQSFSDPYT.

[0307] In some embodiments, the anti-IGSF8 antibody of the present invention comprises a monoclonal antibody or antigen-binding portion / fragment thereof specific for IGSF8 (e.g., specific for the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises: (a) a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 487, 488, and 489, respectively, which are similar to and include HCVR CDR1-3 of monoclonal antibody C36 / 1B4'; and / or (b) a light chain variable region (LCVR) comprising LCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 580, 581, and 582, respectively, which are similar to and include LCVR CDR1-3 of monoclonal antibody C36 / 1B4. SEQ ID NO: 487: GFTFSS Xaa1 A, wherein Xaa1=Y or S; SEQ ID NO: 488: ITGSGGST, and SEQ ID NO: 489: AR Xaa1 Xaa2 Xaa3 Xaa4 L Xaa5 Xaa6, wherein Xaa1 = D or G, Xaa2 = R or absent, Xaa3 = G or C, Xaa4 = A, G or S, Xaa5 = any acidic residue (D / E), and Xaa6 = L, Y, I or V. SEQ ID NO: 580: Xaa1 Xaa2 Xaa3 H Xaa4 Y, wherein Xaa1 = K, Q, P or H, Xaa2 = S, V, I or R, Xaa3 = N, S, L, I or M, Xaa4 = K, N or T, SEQ ID NO: 581: SAS, and Sequence number 582: Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 P Xaa7 Xaa8, wherein Xaa1 = L, Q, K or H, Xaa2 = L, Q, K or H, Xaa3 = S, I or R, Xaa4 = Y or F, Xaa5 = P, N, S or T, Xaa6 = P, N, S or T, Xaa7 = L, I or R, Xaa8 = P, N, S or T.

[0308] In some embodiments, the anti-IGSF8 antibody of the present invention comprises a monoclonal antibody or antigen-binding portion / fragment thereof specific for IGSF8 (e.g., specific for the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises: (a) a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 490, 491, and 492, respectively, which are similar to and include HCVR CDR1-3 of monoclonal antibody C37 / 3F12; and / or (b) a light chain variable region (LCVR) comprising LCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 583, 584, and 585, respectively, which are similar to and include LCVR CDR1-3 of monoclonal antibody C37 / 3F12. SEQ ID NO: 490: GFTFSSYS, SEQ ID NO: 491: ISSSSSYI, SEQ ID NO: 492: Xaa1 RXaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 D Xaa10 Xaa11 Xaa12 Xaa13, wherein Xaa1 = C or G, Xaa2 = P or Q, Xaa3 = Y or D, Xaa4 = Y, A or any acidic residue (D / E), Xaa5 = F or L, Xaa6 = W or L, Xaa7 = S, R or I, Xaa8 = C, V or G, Xaa9 = W, C or L, Xaa10 = W, C or G, Xaa11 = Y, F or V, Xaa12 = D or A, and Xaa13 = H, P or T. SEQ ID NO: 583: Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6, wherein Xaa1 = Q, L, P or any basic residue (R / H / K), Xaa2 = D, S, G, R, T or I, Xaa3 = N, S, L, V, T or I, Xaa4 = H, N, S, G, R, T or I, Xaa5 = N, A, S, E, T, P or I, Xaa6 = Q, D, S or Y, SEQ ID NO: 584: DAS, and Sequence number 585: Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Xaa10, wherein Xaa1 = N, E, Q, L, P or any basic residue (R / H / K), Xaa2 = N, E, Q, L, P or any basic residue (R / H / K), Xaa3 = S, G, R, T or I, Xaa4 = Y, H, D, S or F, Xaa5 = S, G, R, T, I or M, Xaa6 = N, A, S, T, P or I, Xaa7 = H, L, V, R or I, Xaa8 = A, S, Q, T, P or any basic residue (R / H / K), Xaa9 = Y, H, N, S, F or any acidic residue (D / E), Xaa10 = N, A, S, T or P.

[0309] In some embodiments, the anti-IGSF8 antibody of the present invention comprises a monoclonal antibody or antigen-binding portion / fragment thereof specific for IGSF8 (e.g., specific for the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises: (a) a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 493, 494, and 495, respectively, which are similar to and include HCVR CDR1-3 of monoclonal antibody C38 / 2B4; and / or (b) a light chain variable region (LCVR) comprising LCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 586, 587, and 588, respectively, which are similar to and include LCVR CDR1-3 of monoclonal antibody C38 / 2B4. SEQ ID NO: 493: GFT Xaa1 Xaa2 Xaa3 Xaa4 A, wherein Xaa1 = F or C, Xaa2 = R, N or S, Xaa3 = D or S, and Xaa4 = F or Y; SEQ ID NO: 494: I Xaa1 GSGG Xaa2 T, wherein Xaa1 = S or T, and Xaa2 = N, S, or G; Sequence number 495: Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Xaa10 Xaa11 Xaa12 Xaa13 Xaa14 Xaa15, wherein Xaa1 = E, A or S, Xaa2 = R, S or I, Xaa3 = V or G, Xaa4 = A or any acidic residue (D / E), Xaa5 = D, Y or S, Xaa6 = Y or S, Xaa7 = R, S or I, Xaa8 = V, G or C, Xaa9 = L, W, G or C, Xaa10 = P, H or T, Xaa11 = R, S or I, Xaa12 = L, W, C, G or R, Xaa13 = L, F, V or C, Xaa14 = Y, D or A, and Xaa15 = P, H, S or T. SEQ ID NO: 586: Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6, wherein Xaa1 = Q, R or L, Xaa2 = A, S, N or T, Xaa3 = V, F or L, Xaa4 = G or D, Xaa5 = A, S, K, T or P, Xaa6 = Y, L, V, F or I, SEQ ID NO: 587: GVS, and SEQ ID NO: 588: Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 P Xaa7 Xaa8, wherein Xaa1 = K, Q, L or H, Xaa2 = Q, K, H or L, Xaa3 = S, I, T or R, Xaa4 = N, H, D or Q, Xaa5 = V, A or any acidic residue (D / E), Xaa6 = A, G, V, L or F, Xaa7 = G, R or L, Xaa8 = K, S, P or T.

[0310] In some embodiments, the anti-IGSF8 antibody of the present invention comprises a monoclonal antibody or antigen-binding portion / fragment thereof specific for IGSF8 (e.g., specific for the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises: (a) a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 496, 497, and 498, respectively, which are similar to and include HCVR CDR1-3 of monoclonal antibody C39 / 8G4; and / or (b) a light chain variable region (LCVR) comprising LCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 589, 590, and 591, respectively, which are similar to and include LCVR CDR1-3 of monoclonal antibody C39 / 8G4. SEQ ID NO: 496: GFTFSSYA, SEQ ID NO: 497: ITGSGGST, and Sequence number 498: Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 D Xaa7, wherein Xaa1 = A or W, Xaa2 = F, P, R or Y, Xaa3 = D, H, P or S, Xaa4 = R or S, Xaa5 = D, I or N, Xaa6 = L or P, and Xaa7 = S or W. SEQ ID NO: 589: Xaa1 Xaa2 Xaa3 H Xaa4 Y, wherein Xaa1 = K, Q, P or H, Xaa2 = S, V, I or R, Xaa3 = N, S, L, I or M, Xaa4 = K, N or T, SEQ ID NO: 590: AAS, and Sequence number 591: Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 P Xaa7 Xaa8, wherein Xaa1 = L, Q, K or H, Xaa2 = L, Q, K or H, Xaa3 = S, I or R, Xaa4 = Y or F, Xaa5 = P, N, S or T, Xaa6 = P, N, S or T, Xaa7 = L, I or R, Xaa8 = P, N, S or T.

[0311] In the heavy chain only sequence consensus / motif below, the CDR sequences are also based on the IMGT numbering scheme.

[0312] In some embodiments, the anti-IGSF8 antibodies of the present invention comprise a monoclonal antibody or antigen-binding site / fragment thereof specific for IGSF8 (e.g., specific for the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 499, 500, and 501, respectively. SEQ ID NO: 499: GGTFSS Xaa1 G, wherein Xaa1 = Y, N or D, SEQ ID NO: 500: IIPIFGTA, and SEQ ID NO: 501: Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 S Xaa7 Xaa8, wherein Xaa1 = S, E or A, Xaa2 = S, R or I, Xaa3 = Y, A or any acidic residue (D / E), Xaa4 = Y, S, F or D, Xaa5 = S, C or any aromatic residue (F / Y / W), Xaa6 = Y, A or any acidic residue (D / E), Xaa7 = C, V or G, and Xaa8 = Y or D.

[0313] In some embodiments, the anti-IGSF8 antibodies of the present invention comprise a monoclonal antibody or antigen-binding site / fragment thereof specific to IGSF8 (e.g., specific to the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 502, 503, and 504, respectively. SEQ ID NO: 502: Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Y Xaa7, wherein Xaa1 = C, V or G, Xaa2 = Y or S, Xaa3 = P or T, Xaa4 = Y, F, L or I, Xaa5 = N or T, Xaa6 = H, N or K, and Xaa7 = Y or S; SEQ ID NO: 503: INPYTGSA, and Sequence number 504: Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Xaa10 Xaa11 Xaa12 Xaa13 Xaa14, wherein Xaa1 = S, E or A, Xaa2 = S, R, K or G, Xaa3 = H, N, A or any acidic residue (D / E), Xaa4 = S, D, T or A, Xaa5 = P, K or T, Xaa6 = E, R, V or G, Xaa7 = S, H, R or L, Xaa8 = H, N, P, L or Q, Xaa9 = Y, S or D, Xaa10 = H, N, K, I or T, Xaa11 = S, G, V, C or A, Xaa12 = M, R, L or I, Xaa13 = H, N, G, V, Y, A or any acidic residue (D / E), and Xaa14 = I, V, F, L or A.

[0314] In some embodiments, the anti-IGSF8 antibodies of the present invention comprise a monoclonal antibody or antigen-binding site / fragment thereof specific for IGSF8 (e.g., specific for the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 505, 506, and 507, respectively. SEQ ID NO: 505: GFT Xaa1 NSFA, wherein Xaa1 = C, F or V; SEQ ID NO: 506: ISGSGGGT, and SEQ ID NO: 507: Xaa1 Xaa2 D Xaa3 SP Xaa4 Xaa5 Xaa6 Xaa7 SGA Xaa8 D Xaa9, wherein Xaa1 = E or A, Xaa2 = N, K, T or Q, Xaa3 = S, R or L, Xaa4 = Y, S or D, Xaa5 = Y or any acidic residue (D / E), Xaa6 = F or L, Xaa7 = W, L or G, Xaa8 = F, L or I, and Xaa9 = Y, S or D.

[0315] In some embodiments, the anti-IGSF8 antibodies of the present invention comprise a monoclonal antibody or antigen-binding site / fragment thereof specific to IGSF8 (e.g., specific to the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 508, 509, and 510, respectively. SEQ ID NO: 508: Xaa1 FTF Xaa2 Xaa3 Xaa4 Xaa5, wherein Xaa1 = C or G, Xaa2 = N, S or R, Xaa3 = S, N or D, Xaa4 = Y, S or F, and Xaa5 = S or A; SEQ ID NO: 509: I Xaa1 GSGG Xaa2 T, wherein Xaa1 = S or T, and Xaa2 = S, N, T or G, and SEQ ID NO: 510: Xaa1 Xaa2 R Xaa3 Xaa4 Xaa5 F Xaa6 Xaa7 Xaa8 Xaa9 D Xaa10 Xaa11 Xaa12 Xaa13, wherein Xaa1 = E or A, Xaa2 = C or G, Xaa3 = P or Q, Xaa4 = Y or D, Xaa5 = Y or any acidic residue (D / E), Xaa6 = W, L or G, Xaa7 = S, R or I, Xaa8 = C, V or G, Xaa9 = W, C or G, Xaa10 = W, C or G, Xaa11 = F, L or V, Xaa12 = A or any acidic residue (D / E), and Xaa13 = H, P or T.

[0316] In some embodiments, the anti-IGSF8 antibodies of the present invention comprise a monoclonal antibody or antigen-binding site / fragment thereof specific to IGSF8 (e.g., specific to the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 511, 512, and 513, respectively. SEQ ID NO: 511: Xaa1 Xaa2 TF Xaa3 Xaa4 Xaa5 Xaa6, wherein Xaa1 = V or G, Xaa2 = Y, F or L, Xaa3 = N, S or R, Xaa4 = S, N or D, Xaa5 = Y, S or F, and Xaa6 = S, D or A; SEQ ID NO: 512: I Xaa1 GS Xaa2 G Xaa3 T, wherein Xaa1 = S or T, Xaa2 = S or G, and Xaa3 = S, N, T or G, and SEQ ID NO: 513: Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Xaa10 GM Xaa11 Xaa12, wherein Xaa1 = S, E or A, Xaa2 = R, K or T, Xaa3 = N or any acidic residue (D / E), Xaa4 = D, T or A, Xaa5 = K or T, Xaa6 = E, R or G, Xaa7 = H, R or L, Xaa8 = H or P, Xaa9 = Y or D, Xaa10 = S, N, K, I, Y or T, Xaa11 = Y, V or any acidic residue (D / E), and Xaa12 = G, I or V.

[0317] In some embodiments, the anti-IGSF8 antibodies of the present invention comprise a monoclonal antibody or antigen-binding site / fragment thereof specific to IGSF8 (e.g., specific to the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 514, 515, and 516, respectively. SEQ ID NO: 514: GYTL Xaa1 Xaa2 LS, where Xaa1 = S or T, and Xaa2 = any acidic residue (D / E), SEQ ID NO: 515: FDP Xaa1 Xaa2 Xaa3 E Xaa4, where Xaa1 = E or Q, Xaa2 = any acidic residue (D / E), Xaa3 = N or G, and Xaa4 = I or T, and Sequence number 516:A Xaa1 Xaa2 Xaa3 Xaa4 Y Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Xaa10 Y Xaa11 G Xaa12 Xaa13 Xaa14 Xaa15 Xaa16 DV, wherein Xaa1 = N, K or T, Xaa2 = Y or D, Xaa3 = L or V, Xaa4 = W, V or G, Xaa5 = Y, S or D, Xaa6 = Y, S or D, Xaa7 = Y or any acidic residue (D / E), Xaa8 = S, R or I, Xaa9 = S or R, Xaa10 = V or G, Xaa11 = Y, S or D, Xaa12 = R or L, Xaa13 = N or T, Xaa14 = Y, S or D, Xaa15 = V or G, and Xaa16 = M or I.

[0318] In some embodiments, the anti-IGSF8 antibodies of the present invention comprise a monoclonal antibody or antigen-binding site / fragment thereof specific to IGSF8 (e.g., specific to the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 517, 518, and 519, respectively. SEQ ID NO: 517: GYT Xaa1 T Xaa2 Y Xaa3, wherein Xaa1 = F or L, Xaa2 = S, R or N, and Xaa3 = S or G; SEQ ID NO: 518: Xaa1 S Xaa2 Xaa3 Xaa4 G Xaa5 T, wherein Xaa1 = I or V, Xaa2 = T, F, V or A, Xaa3 = Y or N, Xaa4 = S or N, and Xaa5 = N or D, and Sequence number 519: Xaa1 K Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Xaa10 Xaa11 Xaa12 Xaa13 Xaa14 Xaa15 Xaa16 Xaa17 Xaa18 Xaa19 D Xaa20, wherein Xaa1 = E or A, Xaa2 = Y or D, Xaa3 = F, L or V, Xaa4 = V or G, Xaa5 = Y or D, Xaa6 = Y or D, Xaa7 = Y, S or D, Xaa8 = any acidic residue (D / E), Xaa9 = S or R, Xaa10 = S, R or N, Xaa11 = V or G, Xaa12 = Y or D, Xaa13 = Y, S or D, Xaa14 = R or G, Xaa15 = R or L, Xaa16 = N or T, Xaa17 = Y or D, Xaa18 = S, C or G, Xaa19 = M, L or I, and Xaa20 = F, I or V.

[0319] In some embodiments, the anti-IGSF8 antibodies of the present invention comprise a monoclonal antibody or antigen-binding site / fragment thereof specific to IGSF8 (e.g., specific to the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 520, 521, and 522, respectively. SEQ ID NO: 520: Xaa1 Xaa2 T Xaa3 Xaa4 DYXaa5, wherein Xaa1 = R or G, Xaa2 = F or L, Xaa3 = C, F or V, Xaa4 = N or D, and Xaa5 = S or A; SEQ ID NO: 521: I Xaa1 WNSG Xaa2 I, wherein Xaa1=S or T, and Xaa2=S, H, or R, and SEQ ID NO: 522: Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 F Xaa7 Xaa8 Xaa9 Xaa10 Xaa11 Xaa12 Xaa13 D Xaa14, wherein Xaa15 = E or A, Xaa16 = C or G, Xaa17 = R or L, Xaa18 = P or Q, Xaa19 = Y or D, Xaa20 = any acidic residue (D / E), Xaa21 = W or G, Xaa22 = S or R, Xaa23 = C or G, Xaa24 = G, L, C or any aromatic residue (F / Y / W), Xaa25 = H or any acidic residue (D / E), Xaa26 = W or G, Xaa27 = C, F or V, and Xaa28 = L or P.

[0320] In some embodiments, the anti-IGSF8 antibodies of the present invention comprise a monoclonal antibody or antigen-binding site / fragment thereof specific to IGSF8 (e.g., specific to the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 523, 524, and 525, respectively. SEQ ID NO: 523: RFTFDDY Xaa1, wherein Xaa1 = S or A, SEQ ID NO: 524: ISWNSGRI, and SEQ ID NO: 525: ARYG Xaa1 P Xaa2 Xaa3 Xaa4 D Xaa5, wherein Xaa1 = Y or D, Xaa2 = C, F or V, Xaa3 = Y, S or D, Xaa4 = C, F or L, and Xaa5 = Y, S or D.

[0321] In some embodiments, the anti-IGSF8 antibodies of the present invention comprise a monoclonal antibody or antigen-binding site / fragment thereof specific to IGSF8 (e.g., specific to the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 526, 527, and 528, respectively. SEQ ID NO: 526: Xaa1 Xaa2 Xaa3 F Xaa4 NY Xaa5, wherein Xaa1 = V or G, Xaa2 = Y or S, Xaa3 = Y or S, Xaa4 = S or R, and Xaa5 = W, C, or L; SEQ ID NO: 527: IDPSNSYT, and SEQ ID NO: 528: A Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Xaa10 Xaa11 D Xaa12, wherein Xaa1 = S or R, Xaa2 = A or any acidic residue (D / E), Xaa3 = R, L, I or A, Xaa4 = K, T or A, Xaa5 = A, T or G, Xaa6 = S, C, R or G, Xaa7 = R, H or N, Xaa8 = Y, S or D, Xaa9 = N, K, or absent, Y or T, Xaa10 = C or G, Xaa11 = M or R, and Xaa12 = F, V or G.

[0322] In some embodiments, the anti-IGSF8 antibodies of the present invention comprise a monoclonal antibody or antigen-binding site / fragment thereof specific to IGSF8 (e.g., specific to the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 529, 530, and 531, respectively. SEQ ID NO: 529: GFTF Xaa1 Xaa2 Xaa3 Xaa4, wherein Xaa1 = S or N, Xaa2 = S or N, Xaa3 = Y or F, and Xaa4 = S or A; SEQ ID NO: 530: I Xaa1 Xaa2 S Xaa3 Xaa4 Xaa5 T, wherein Xaa1 = S, N or T, Xaa2 = A or G, Xaa3 = S or G, Xaa4 = T or G, and Xaa5 = S, R, T or G, and SEQ ID NO: 531: A Xaa1 DLGY Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 GY Xaa7 Xaa8 Xaa9 Xaa10 Xaa11 G Xaa12 Xaa13 V, wherein Xaa1 = K or T, Xaa2 = Y or D, Xaa3 = Y or D, Xaa4 = any acidic residue (D / E), Xaa5 = S, R or I, Xaa6 = S or R, Xaa7 = Y or S, Xaa8 = E, R or G, Xaa9 = H or R, Xaa10 = N, K or T, Xaa11 = Y, S or D, Xaa12 = M or I, and Xaa13 = N or D.

[0323] In some embodiments, the anti-IGSF8 antibodies of the present invention comprise a monoclonal antibody or antigen-binding site / fragment thereof specific to IGSF8 (e.g., specific to the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 532, 533, and 534, respectively. SEQ ID NO: 532: GFTF Xaa1 Xaa2 Xaa3 Xaa4, where Xaa1 = N, S or R, Xaa2 = S or D, Xaa3 = Y or F, and Xaa4 = S or A; SEQ ID NO: 533: I Xaa1 Xaa2 S Xaa3 Xaa4 Xaa5 T, wherein Xaa1 = S, N or T, Xaa2 = A or G, Xaa3 = S or G, Xaa4 = T or G, and Xaa5 = S, N, G, R or T, and SEQ ID NO: 534: A Xaa1 RG Xaa2 Y Xaa3 Xaa4 S Xaa5 Xaa6 Xaa7 YR Xaa8 Xaa9 R Xaa10 Xaa11 Xaa12 Xaa13 Xaa14, wherein Xaa1 = S or R, Xaa2 = any acidic residue (D / E), Xaa3 = Y, S or D, Xaa4 = S, T or A, Xaa5 = E, V or G, Xaa6 = S or R, Xaa7 = Y or S, Xaa8 = H or P, Xaa9 = H or R, Xaa10 = Y or D, Xaa11 = C, D or G, Xaa12 = M or L, Xaa13 = N or D, and Xaa14 = I or V.

[0324] In some embodiments, the anti-IGSF8 antibodies of the present invention comprise a monoclonal antibody or antigen-binding site / fragment thereof specific for IGSF8 (e.g., specific for the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 535, 536, and 537, respectively. SEQ ID NO: 535: G Xaa1 Xaa2 FTRYG, wherein Xaa1=Y or S, and Xaa2=N or T; SEQ ID NO: 536: ISTYSGNT, and SEQ ID NO: 537: Xaa1 R Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Xaa10 Xaa11 Xaa12 Xaa13, wherein Xaa1 = S or A, Xaa2 = A, S or any acidic residue (D / E), Xaa3 = R, L, I or A, Xaa4 = S, T or A, Xaa5 = S, A, T or G, Xaa6 = G, R, V, D or C, Xaa7 = Y, H, R or Q, Xaa8 = Y, S or D, Xaa9 = Y, N or absent, Xaa10 = C, V or G, Xaa11 = M or I, Xaa12 = any acidic residue (D / E), and Xaa13 = I or V.

[0325] In some embodiments, the anti-IGSF8 antibodies of the present invention comprise a monoclonal antibody or antigen-binding site / fragment thereof specific for IGSF8 (e.g., specific for the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 538, 539, and 540, respectively. SEQ ID NO: 538: G Xaa1 TFSTYG, wherein Xaa1 = F or V; SEQ ID NO: 539: IWDDGSYK, and SEQ ID NO: 540: A Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Xaa10 Xaa11 Xaa12 D Xaa13, wherein Xaa1 = S, R or I, Xaa2 = S or A, Xaa3 = M or R, Xaa4 = Y or S, Xaa5 = P or T, Xaa6 = M, R, L or I, Xaa7 = S, D or A, Xaa8 = R or L, Xaa9 = R, L or I, Xaa10 = W, V or G, Xaa11 = W, C, L or G, Xaa12 = F, L or V, and Xaa13 = H, P or T.

[0326] In some embodiments, the anti-IGSF8 antibodies of the present invention comprise a monoclonal antibody or antigen-binding site / fragment thereof specific to IGSF8 (e.g., specific to the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 541, 542, and 543, respectively. SEQ ID NO: 541: GFTF Xaa1 Xaa2 Xaa3 A, where Xaa1 = N, S or R, Xaa2 = S or D, and Xaa3 = Y or F; SEQ ID NO: 542: I Xaa1 Xaa2 SG Xaa3 Xaa4 T, wherein Xaa1 = S, N or T, Xaa2 = A or G, Xaa3 = T or G, and Xaa4 = S, R, N or G, and Sequence number 543: ARDS Xaa1 VAS Xaa2 GRG Xaa3 V Xaa4 H Xaa5 Xaa6 GM Xaa7 V, wherein Xaa1 = H, N or T, Xaa2 = T, K or Q, Xaa3 = V or G, Xaa4 = Y or D, Xaa5 = Y, S or D, Xaa6 = H or P, and Xaa7 = N or D.

[0327] In some embodiments, the anti-IGSF8 antibodies of the present invention comprise a monoclonal antibody or antigen-binding site / fragment thereof specific for IGSF8 (e.g., specific for the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 544, 545, and 546, respectively. SEQ ID NO: 544: Xaa1 FTF Xaa2 Xaa3 Y Xaa4, wherein Xaa1 = R or G, Xaa2 = N or D, Xaa3 = Y or D, and Xaa4 = S or A; SEQ ID NO: 545: ISWNSG Xaa1 I, wherein Xaa1=S or R, and SEQ ID NO: 546: A Xaa1 Xaa2 R Xaa3 Xaa4 D Xaa5, wherein Xaa1 = R or L, Xaa2 = S, V or G, Xaa3 = T, H, N or Q, Xaa4 = R, L or V, and Xaa5 = S, K, Y, Q, T or A.

[0328] In some embodiments, the anti-IGSF8 antibodies of the present invention comprise a monoclonal antibody or antigen-binding site / fragment thereof specific for IGSF8 (e.g., specific for the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 547, 548, and 549, respectively. SEQ ID NO: 547: GYTFTNYY, SEQ ID NO: 548: INPYTGSA, and SEQ ID NO: 549: ARDP Xaa1 G Xaa2 VNH Xaa3 Y Xaa4 Xaa5 D Xaa6, wherein Xaa1 = C, F, L or V, Xaa2 = V or G, Xaa3 = F or L, Xaa4 = Y, S or D, Xaa5 = M, R, L or I, and Xaa6 = V or G.

[0329] In some embodiments, the anti-IGSF8 antibodies of the present invention comprise a monoclonal antibody or antigen-binding site / fragment thereof specific for IGSF8 (e.g., specific for the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 550, 551, and 552, respectively. SEQ ID NO: 550: GGSFSGYY, SEQ ID NO: 551: INHSGST, and SEQ ID NO: 552: Xaa1 Xaa2 P Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 ES Xaa8 Xaa9 Xaa10 Xaa11 Xaa12 D Xaa13, wherein Xaa1 = E or A, Xaa2 = M or R, Xaa3 = Y, S or D, Xaa4 = H, N or T, Xaa5 = S or R, Xaa6 = S or A, Xaa7 = W, C or L, Xaa8 = Y, S or D, Xaa9 = Y, S or D, Xaa10 = Y, S or D, Xaa11 = V or G, Xaa12 = M, R or L, and Xaa13 = F or V.

[0330] In some embodiments, the anti-IGSF8 antibodies of the present invention comprise a monoclonal antibody or antigen-binding site / fragment thereof specific for IGSF8 (e.g., specific for the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 553, 554, and 555, respectively. SEQ ID NO: 553: GYTFTNYY, SEQ ID NO: 554: INPYTGSA, and Sequence number 555: AR Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Xaa10 Xaa11, wherein Xaa1 = S, F, V or A, Xaa2 = R, L or I, Xaa3 = G or A, Xaa4 = S, T or A, Xaa5 = C, I or G, Xaa6 = R or L, Xaa7 = Y, S or D, Xaa8 = C, D, V or G, Xaa9 = M, R or I, Xaa10 = N or D, and Xaa11 = I or V.

[0331] In some embodiments, the anti-IGSF8 antibodies of the present invention comprise a monoclonal antibody or antigen-binding site / fragment thereof specific to IGSF8 (e.g., specific to the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 556, 557, and 558, respectively. SEQ ID NO: 556: GFT Xaa1 NSFA, wherein Xaa1=F or V; SEQ ID NO: 557: ISGSGGGT, and Sequence number 558: A Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7, wherein Xaa1 = R or L, Xaa2 = S, W or G, Xaa3 = R or L, Xaa4 = T, H, N or Q, Xaa5 = G, R, I, V or L, Xaa6 = any acidic residue (D / E), and Xaa7 = S, K or T.

[0332] In some embodiments, the anti-IGSF8 antibodies of the present invention comprise a monoclonal antibody or antigen-binding site / fragment thereof specific for IGSF8 (e.g., specific for the Ig-V set domain or the D1 domain of the ECD of IGSF8), wherein the monoclonal antibody comprises a heavy chain variable region (HCVR) comprising HCVR CDR1, CDR2, and CDR3 of SEQ ID NOs: 559, 560, and 561, respectively. SEQ ID NO: 559: G Xaa1 TFTRY Xaa2, wherein Xaa1 = Y or S, and Xaa2 = C or G; SEQ ID NO: 560: ISTYSGNT, and SEQ ID NO: 561: A Xaa1 G Xaa2 Xaa3 P Xaa4 R Xaa5 H Xaa6 Xaa7 Xaa8 Xaa9 Xaa10, wherein Xaa1 = R or K, Xaa2 = W, V or G, Xaa3 = R or L, Xaa4 = Y, S or D, Xaa5 = W, V or G, Xaa6 = Y or D, Xaa7 = C, D or G, Xaa8 = M or I, Xaa9 = N or any acidic residue (D / E), and Xaa10 = F, I or V.

[0333] In some embodiments, the present invention provides an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof specific to IGSF8, wherein the monoclonal antibody comprises: (1) a heavy chain variable region (HCVR) comprising an HCVR CDR1-CDR3 sequence that is at least 95% (e.g., 100%) identical to, or has up to 1, 2, 3, 4, 5, 6, 7, 8, or 9 substitutions with, the HCVR CDR1-CDR3, respectively, of any one of antibodies C1 to C39, e.g., C30 to C39; and (2) a light chain variable region (LCVR) comprising an LCVR CDR1-CDR3 sequence that is at least 95% (e.g., 100%) identical to, or has up to 1, 2, 3, 4, 5, 6, 7, 8, or 9 substitutions with, the LCVR CDR1-CDR3, respectively, of any one of antibodies C1 to C39, e.g., C30 to C39. In certain embodiments, the anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof has the HCVR CDR1-CDR3 and LCVR CDR1-CDR3 of one of antibodies C1 to C39, for example, any one of C30 to C39.

[0334] In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises (a) an HCVR sequence at least 95% (e.g., 100%) identical to the HCVR sequence of any one of antibodies C1 to C39, e.g., C30 to C39; and / or (b) an LCVR sequence at least 95% (e.g., 100%) identical to the LCVR sequence of any one of antibodies C1 to C39, e.g., C30 to C39. In certain embodiments, the anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof has the HCVR and LCVR of one of antibodies C1 to C39, e.g., any one of C30 to C39.

[0335] In some embodiments, the present invention provides an anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof specific for IGSF8, comprising: (1) a heavy chain variable region (HCVR) comprising the HCVR CDR1-CDR3 sequence of any one of antibodies C1 to C39, e.g., C30 to C39, with substitutions of up to 1, 2, or 3 residues compared to the HCVR CDR1-CDR3, respectively; and (2) a light chain variable region (LCVR) comprising the LCVR CDR1-CDR3 sequence of any one of antibodies C1 to C39, e.g., C30 to C39, with substitutions of up to 1, 2, or 3 residues compared to the LCVR CDR1-CDR3, respectively. In some embodiments, when a CDR has only 5, 4, or 3 residues, substitutions other than conservative substitutions are not allowed (e.g., up to 1 or 2 conservative substitutions in a CDR with 5, 4, or 3 or fewer residues).

[0336] High-affinity IGSF8 antibody based on comprehensive CDR mutagenesis analysis To determine the relative importance of each CDR region residue, as well as the framework region residues surrounding the CDR regions, and to identify key residues important (or unimportant) for IGSF8 binding, two specific high-affinity antibodies were selected for further CDR region sequence analysis. Specifically, each existing residue in the two lead antibodies was individually replaced with 19 other amino acids to generate all possible mutants and evaluate the impact of such substitutions. Figures 29-36 summarize the results for each substitution. Based on this study, consensus sequences representing all acceptable substitutions (e.g., those that do not substantially affect antigen binding) as well as favorable substitutions (e.g., those that increase antigen binding compared to the original sequence) were constructed and are presented herein.

[0337] Thus, the present disclosure includes amino acid consensus sequences for CDR region sequences (in some cases surrounding framework region sequences based on the IMGT numbering scheme), which indicate specific amino acids (indicated using the variable "X" or "Xaa") that may be modified or substituted in antibody amino acid sequences, e.g., as set forth in Tables A1 and A2. Unless explicitly indicated, all antibody and CDR sequences are annotated using the IMGT numbering scheme.

[0338] Related CDR sequences that may appear in the same VH and / or VL sequence of an antibody are grouped together in the same row. For example, an antibody of the present invention may comprise any one of VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3, where the VH CDR1-VH CDR3 and VL CDR1-VL CDR3 are represented by SEQ ID NOs: 714, 715, 716, 717, 718, and 719, respectively.

[0339] Furthermore, the amino acids at each Xi position (where i=1, 2, 3, . . .) can be a selected subset of amino acids as specified in each consensus sequence. It is anticipated that any one or more of the specific amino acids listed at each Xi position can be an allowed value at that Xi position. For example, in SEQ ID NO: 714, X2 can be any residue, such as A, C, D, E, F, G, H, K, M, N, P, Q, R, T, or W. In some embodiments, X2 is A or C, F or G; M, N, or Q, etc.

[0340] Unless explicitly stated, all antibody and CDR sequences are annotated according to the IMGT numbering scheme.

[0341] [Table 1-1]

[0342] [Table 1-2]

[0343] [Table 1-3]

[0344] [Table 1-4]

[0345] [Table 1-5]

[0346] [Table 1-6]

[0347] [Table 1-7]

[0348] [Table 1-8]

[0349] [Table 1-9]

[0350] [Table 1-10]

[0351] [Table 1-11]

[0352] [Table 1-12]

[0353] In certain embodiments, in any of the Xi residue definitions in Table A1, the residue following "for example" has enhanced binding compared to the original residue at the same position. Table A2 provides antibody consensus sequences with such enhanced binding.

[0354] [Table 2-1]

[0355] [Table 2-2]

[0356] [Table 2-3]

[0357] [Table 2-4]

[0358] [Table 2-5]

[0359] [Table 2-6]

[0360] [Table 2-7]

[0361] [Table 2-8]

[0362] Thus, in certain embodiments, the anti-IGSF8 antibody or antigen-binding fragment thereof comprises VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 that comprise, consist essentially of, or consist of the amino acid sequences of SEQ ID NOs: 714, 715, 716, 717, 718, and 719, respectively.

[0363] In certain embodiments, the anti-IGSF8 antibody or antigen-binding fragment thereof comprises VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 that comprise, consist essentially of, or consist of the amino acid sequences of SEQ ID NOs: 720, 721, 722, 723, 724, and 725, respectively.

[0364] In certain embodiments, the anti-IGSF8 antibody or antigen-binding fragment thereof comprises VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 that comprise, consist essentially of, or consist of the amino acid sequences of SEQ ID NOs: 754, 755, 756, 757, 758, and 759, respectively.

[0365] In certain embodiments, the anti-IGSF8 antibody or antigen-binding fragment thereof comprises VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 that comprise, consist essentially of, or consist of the amino acid sequences of SEQ ID NOs: 760, 761, 762, 763, 764, and 765, respectively.

[0366] In certain embodiments, the anti-IGSF8 antibody or antigen-binding fragment thereof comprises a VH comprising, consisting essentially of, or consisting of the amino acid sequences of SEQ ID NOs: 734, 735, and 736; and a VL comprising, consisting essentially of, or consisting of the amino acid sequences of SEQ ID NOs: 737, 738, and 739, respectively.

[0367] In certain embodiments, the anti-IGSF8 antibody or antigen-binding fragment thereof comprises a VH comprising, consisting essentially of, or consisting of the amino acid sequences of SEQ ID NOs: 740, 741, and 742; and a VL comprising, consisting essentially of, or consisting of the amino acid sequences of SEQ ID NOs: 743, 744, and 745, respectively.

[0368] In certain embodiments, the anti-IGSF8 antibody or antigen-binding fragment thereof comprises a VH comprising, consisting essentially of, or consisting of the amino acid sequences of SEQ ID NOs: 774, 775, and 776; and a VL comprising, consisting essentially of, or consisting of the amino acid sequences of SEQ ID NOs: 777, 778, and 779, respectively.

[0369] In certain embodiments, the anti-IGSF8 antibody or antigen-binding fragment thereof comprises a VH comprising, consisting essentially of, or consisting of the amino acid sequences of SEQ ID NOs: 780, 781, and 782; and a VL comprising, consisting essentially of, or consisting of the amino acid sequences of SEQ ID NOs: 783, 784, and 785, respectively.

[0370] For example, in some embodiments, the anti-IGSF8 antibody or antigen-binding fragment thereof is (i) a VH CDR1 comprising, consisting essentially of, or consisting of the amino acid sequence X1-X2-X3-X4-X5-X6-X7-X8 (SEQ ID NO: 714), wherein: X1 is A, E, F, G, H, I, K, L, M, N, P, Q, R, T, V, W or Y; X2 is A, C, D, E, F, G, H, K, M, N, P, Q, R, T or W; X3 is A, C, D, E, F, G, H, K, L, M, P, Q, R, T, V, W or Y; X4 is A, C, D, E, F, G, H, K, M, N, P, Q, R, T or W; X5 is A, C, D, E, G, H, I, K, L, M, N, Q, R, S, V or W; X6 is C, D, E, F, G, H, I, L, N, P, Q, T, V, W or Y; X7 is A, D, E, F, G, I, K, L, M, P, Q, R, S, T, V, W or Y; X8 is E, F, G, H, I, K, L, M, N, P, Q, R, T, W or Y); (ii) a VH CDR2 comprising, consisting essentially of, or consisting of the amino acid sequence X3-X4-X5-X6-X7-X8-X9-X10 (SEQ ID NO: 715), wherein: X3 is A, C, D, E, G, H, I, K, L, M, P, Q, R, W or Y; X4 is A, D, E, F, H, I, K, M, N, P, Q, R, T, V, W or Y, for example R; X5 is C or D, X6 is A, D, E, F or G, for example G, E or A, most preferably G; X7 is D, E, F, G, H, I, K, L, M, N, P, Q, T, W or Y; X8 is C, F, H, K, P, R, S, T, W or Y, for example K or R, most preferably K; X9 is A, D, E, F, G, I, K, L, M, P, Q, R, T, V, W or Y; X10 is A, C, D, F, G, H, I, K, L, P, Q, S, V, W or Y); (iii) a VH CDR3 comprising, consisting essentially of, or consisting of the amino acid sequence X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (SEQ ID NO: 716), wherein: X1 is A, C, D, F, G, H, I, K, L, M, N, Q, R, W or Y; X2 is A, C, D, E, F, H, L, M, N, P, Q, R, V, W or Y; X3 is C, D, F, I or Q; X4 is E, F, G, H, I, K, L, M, N, P or Q; X5 is A, D, E, F, H, I, K, L, M, P, Q, S, T, V, W or Y; X6 is A, E, F, G, H, I, K, L, M, N, P, Q, R, T, W or Y; X7 is A, D, E, F, H, I, M, N, P, Q, S, T, V, W or Y, for example Y; X8 is A, C, D, F, G, H, I, K, L, M, N, P, Q, S, T, W or Y; X9 is A, E, G, I, K, L, M, P, Q, R, T, V, W or Y; X10 is A, C, E, F, H, I, K, L, M, N, Q or R; X11 is D, F, G, H, M, N, P, R, T or W; X12 is C, D, F, K, L, M, P, Q, R or W, for example R or K; X13 is G, H, I, K, M, P, Q, R, W or Y); (iv) a VL CDR1 comprising, consisting essentially of, or consisting of the amino acid sequence X4-X5-X6-X7-X8-X9 (SEQ ID NO: 717), wherein: X4 is A, C, D, E, F, G, I, K, L, M, N, Q, S, T, V, W or Y; X5 is A, C, D, E, F, H, I, K, L, M, N, P, Q, R, T, V or W; X6 is A, C, D, E, F, G, H, I, K, M, P, Q, R, V, W or Y; X7 is C, D, E, F, G, K, L, M, R, S, T, V, W or Y, for example E, G, K, M, T, V or W; X8 is C, D, E, F, G, H, I, L, M, P, Q, S, T, V, W or Y, for example D, F, G, L, M, P, Q, S, T, V, W or Y; X9 is A, C, F, G, H, I, Q, S, T, W or Y, for example, A, C, G, Q, S, T or W, most preferably W); (v) a VL CDR2 comprising, consisting essentially of, or consisting of the amino acid sequence X6-X7-X8 (SEQ ID NO: 718), wherein: X6 is A, C, D, F, G, H, N, R or S, for example A, G, H, N, R or S, most preferably G; X7 is A, C, D, I, K, S or T, for example D, S or T, most preferably S; X8 is A, C, D, E, F, H, I, N, P, S, T, V or W, for example, A, D, E, F, H, N, P, T, V or W, most preferably P) (vi) a VL CDR3 comprising, consisting essentially of, or consisting of the amino acid sequence X1-X2-X3-X4-X5-X6-X7-X8-X9 (SEQ ID NO: 719), wherein: X1 is A, C, D, E, F, G, I, M, N, P, Q, S, T, V, W or Y; X2 is A, C, D, E, F, G, I, M, N, P, Q, S, T, V, W or Y; X3 is A, C, D, E, G, I, K, L, M, N, P, Q, R, T, V, W or Y; X4 is D, E, F, P, Q or Y, for example E, Q or Y; X5 is G, K, L, M, N, P, Q, R or S, for example G, R or K; X6 is C, D, E, F, H, I, L, M, N, P, Q, S, T, V or Y, for example D, E, L, M, N, Q, S, T or V; X7 is A, C, D, E, F, G, I, K, L, M, N, P, Q, R, V, W or Y; X8 is A, E, F, G, I, K, M, N, P, Q, R, T, V, W or Y; X9 is C, D, E, F, G, H, I, K, L, M, N, Q, R, T, V, W or Y) Includes:

[0371] As another example, in some embodiments, the anti-IGSF8 antibody or antigen-binding fragment thereof may be (i) a VH CDR1 comprising, consisting essentially of, or consisting of the amino acid sequence X1-X2-X3-X4-X5-X6-X7-X8 (SEQ ID NO: 720), wherein: X1 is A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W or Y, for example R; X2 is A, C, D, E, F, G, H, K, L, M, N, P, Q, R, S, T, V or W, for example G; X3 is A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, T, V, W or Y; X4 is A, C, D, E, F, G, H, I, K, M, N, P, Q, R, S, T, V, W or Y; X5 is I, K, L, M, P, Q, V, W or Y, for example K; X6 is F, G, H, I, K, L, M, P, Q, T, V, W or Y; X7 is A, C, D, E, F, G, H, I, K, M, N, P, Q, R, S, T, V, W or Y, for example F, S or N, more preferably F; X8 is A, C, D, E, F, H, K, L, M, N, P, Q, R, T or V); (ii) a VH CDR2 comprising, consisting essentially of, or consisting of the amino acid sequence X2-X3-X4-X5-X6-X7-X8-X9 (SEQ ID NO: 721), wherein: X2 is A, C, D, E, G, H, I, K, L, M, N, P, Q, R, S, T, V, W or Y; X3 is A, C, E, F, G, H, I, K, L, M, P, Q, R, S, V or Y; X4 is C, D, E, F, G, H, I, K, L, M, N, Q, R, S or V; X5 is A, C, F, H, K, L, M, P, Q, R, S, T, V or W, for example M; X6 is A, C, E, F, G, H, I, K, L, M, P, Q, R, V or W, for example F; X7 is A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, T, V, W or Y; X8 is A, C, F, G, I, K, L, M, N, P, Q, R, S, T, V, W or Y, for example G, N, R, S or T, more preferably G or S; X9 is C, D, E, F, G, H, K, L, M, N, P, Q, S, T, V, W or Y); (iii) a VH CDR3 comprising, consisting essentially of, or consisting of the amino acid sequence X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15 (SEQ ID NO: 722), wherein: X1 is A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W or Y; X2 is F, G, H, I or T; X3 is A, C, D, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W or Y; X4 is D, E, F, H, N, Q, R, S, T, V, W or Y, for example D; X5 is A, H, I, L, M, N, Q or Y; X6 is A, C, D, F, G, H, K, M, N, P, Q, R, S, T, V or Y; X7 is A, C, E, F, H, K, M, N, P, Q, S, T, W or Y; X8 is A, C, D, E, F, G, H, I, K, L, M, N, P, Q, S, T, V or W, X9 is A, C, D, E, F, H, I, K, L, N, Q, R, S, V, W or Y; X10 is A, C, D, E, F, H, I, K, L, M, N, P, Q, R, S, V, W or Y; X11 is A, C, E, F, H, I, K, L, M, N, P, Q, S, T, V, W or Y; X12 is F, H, I, K, N, P, Q, R, V, W or Y, for example F or Y; X13 is A, C, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, W or Y; X14 is D, F, G, H, P, Q or T, for example T; X15 is D, E, F, G, I, K, L, N, P, Q, R, S, or T); (iv) a VL CDR1 comprising, consisting essentially of, or consisting of the amino acid sequence X4-X5-X6-X7-X8-X9 (SEQ ID NO: 723), wherein: X4 is A, C, D, E, F, G, I, K, M, N, R, S, T, V, W or Y, for example E; X5 is C, D, E, H, K, L, M, Q, T, W or Y, for example D; X6 is A, C, D, E, F, G, H, K, M, N, P, Q, R, T, V, W or Y; X7 is C, E, G, I, L, M, P, Q, V, W or Y; X8 is C, M, P, Q, T or W, for example P; X9 is A, C, E, F, G, I, K, L, M, N, P, Q, R, T, V or Y, for example, Y); (v) a VL CDR2 comprising, consisting essentially of, or consisting of the amino acid sequence X6-X7-X8 (SEQ ID NO: 724), wherein: X6 is C, H, I, L, M, N, P, Q, W or Y, for example H or Q; X7 is C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W or Y, for example S, T or V, more preferably S or T; X8 is C, D, E, G, H, I, K, L, M, P, Q, R, S, W or Y); and (vi) a VL CDR3 comprising, consisting essentially of, or consisting of the amino acid sequence X1-X2-X3-X4-X5-X6-X7-X8-X9 (SEQ ID NO: 725), wherein: X1 is C, D, F, G, I, K, M, N, P, Q, S, T, V, W or Y; X2 is A, C, D, F, G, I, L, M, N, P, Q, R, S, T, V or W; X3 is C, E, G, K, M, P, S, V or W; X4 is C, H, L, M, P, Q, R, V or W, for example P; X5 is C, D, E, F, L, M, P, V or W, for example F; X6 is A, C, E, G, H, K, M, N, P, Q, R, V or W, for example, A, N, P, R or W; X7 is A, C, D, E, G, H, I, K, M, N, P, R, S, T, V, W or Y; X8 is A, C, D, E, G, K, M, N, P, Q, R, S or W, for example D, P, S or W; X9 is C, D, E, F, G, H, K, L, M, Q, R, T, V, W or Y) Includes:

[0372] In some embodiments, an anti-IGSF8 antibody or antigen-binding fragment thereof of the invention (e.g., having the consensus CDR sequences described above) comprises at least one, two, or three (e.g., all three) corresponding VH CDRs of any one of the antibodies listed in Tables D and G.

[0373] For example, in one embodiment, an antibody of the invention may have a VH CDR1 sequence identical to the VH CDR1 sequence of any one of the antibodies listed in Table D. In one embodiment, an antibody of the invention may have a VH CDR2 sequence identical to the VH CDR2 sequence of any one of the antibodies listed in Table D. In one embodiment, an antibody of the invention may have a VH CDR3 sequence identical to the VH CDR3 sequence of any one of the antibodies listed in Table D.

[0374] In another embodiment, an antibody of the invention may have a VH CDR1 sequence identical to the VH CDR1 sequence of any one of the first antibodies listed in Table D; and a VH CDR2 sequence identical to the VH CDR2 sequence of any one of the second antibodies listed in Table D, wherein the first and second antibodies are the same or different. In another embodiment, an antibody of the invention may have a VH CDR1 sequence identical to the VH CDR2 sequence of any one of the first antibodies listed in Table D; and a VH CDR3 sequence identical to the VH CDR3 sequence of any one of the second antibodies listed in Table D, wherein the first and second antibodies are the same or different. In another embodiment, an antibody of the invention may have a VH CDR2 sequence identical to the VH CDR2 sequence of any one of the first antibodies listed in Table D; and a VH CDR3 sequence identical to the VH CDR3 sequence of any one of the second antibodies listed in Table D, wherein the first and second antibodies are the same or different.

[0375] In yet another embodiment, an antibody of the invention may have a VH CDR1 sequence identical to the VH CDR1 sequence of any one of the first antibodies listed in Table D; a VH CDR2 sequence identical to the VH CDR2 sequence of any one of the second antibodies listed in Table D; and a VH CDR3 sequence identical to the VH CDR3 sequence of any one of the third antibodies listed in Table D, wherein the first, second, and third antibodies are the same or different (e.g., two from the same antibody and one from another antibody, or all three from different antibodies).

[0376] In some embodiments, an anti-IGSF8 antibody or antigen-binding fragment thereof of the invention (e.g., having the consensus CDR sequences described above) comprises at least one, two, or three (e.g., all three) corresponding VH CDRs of any one of the antibodies listed in Table G.

[0377] For example, in one embodiment, an antibody of the invention may have a VH CDR1 sequence identical to the VH CDR1 sequence of any one of the antibodies listed in Table G. In one embodiment, an antibody of the invention may have a VH CDR2 sequence identical to the VH CDR2 sequence of any one of the antibodies listed in Table G. In one embodiment, an antibody of the invention may have a VH CDR3 sequence identical to the VH CDR3 sequence of any one of the antibodies listed in Table G.

[0378] In another embodiment, an antibody of the invention may have a VH CDR1 sequence identical to the VH CDR1 sequence of any one of the first antibodies listed in Table G; and a VH CDR2 sequence identical to the VH CDR2 sequence of any one of the second antibodies listed in Table G, wherein the first and second antibodies are the same or different. In another embodiment, an antibody of the invention may have a VH CDR1 sequence identical to the VH CDR2 sequence of any one of the first antibodies listed in Table G; and a VH CDR3 sequence identical to the VH CDR3 sequence of any one of the second antibodies listed in Table G, wherein the first and second antibodies are the same or different. In another embodiment, an antibody of the invention may have a VH CDR2 sequence identical to the VH CDR2 sequence of any one of the first antibodies listed in Table G; and a VH CDR3 sequence identical to the VH CDR3 sequence of any one of the second antibodies listed in Table G, wherein the first and second antibodies are the same or different.

[0379] In yet another embodiment, an antibody of the invention may have a VH CDR1 sequence identical to the VH CDR1 sequence of any one of the first antibodies listed in Table G; a VH CDR2 sequence identical to the VH CDR2 sequence of any one of the second antibodies listed in Table G; and a VH CDR3 sequence identical to the VH CDR3 sequence of any one of the third antibodies listed in Table G, wherein the first, second, and third antibodies are the same or different (e.g., two from the same antibody and one from another antibody, or all three from different antibodies).

[0380] In some embodiments, the VH CDR1, VH CDR2, and / or VH CDR3 of an anti-IGSF8 antibody or antigen-binding fragment thereof of the invention (e.g., one having the consensus CDR sequences described above) each or collectively has one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, compared to the amino acid sequence of the corresponding VH CDR1, VH CDR2, and / or VH CDR3 of any one of the antibodies listed in Table D.

[0381] In some embodiments, the VH CDR1, VH CDR2, and / or VH CDR3 of an anti-IGSF8 antibody or antigen-binding fragment thereof of the invention (e.g., having the consensus CDR sequences described above) each or collectively has one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, compared to the amino acid sequence of the corresponding VH CDR1, VH CDR2, and / or VH CDR3 of any one of the antibodies listed in Table G.

[0382] In some embodiments, an anti-IGSF8 antibody or antigen-binding fragment thereof of the invention (e.g., having the consensus CDR sequences described above) comprises at least one, two, or three (e.g., all three) corresponding VL CDRs of any one of the antibodies listed in Table D.

[0383] For example, in one embodiment, an antibody of the invention may have a VL CDR1 sequence identical to the VL CDR1 sequence of any one of the antibodies listed in Table D. In one embodiment, an antibody of the invention may have a VL CDR2 sequence identical to the VL CDR2 sequence of any one of the antibodies listed in Table D. In one embodiment, an antibody of the invention may have a VL CDR3 sequence identical to the VL CDR3 sequence of any one of the antibodies listed in Table D.

[0384] In another embodiment, an antibody of the invention may have a VL CDR1 sequence identical to the VL CDR1 sequence of any one of the first antibodies listed in Table D; and a VL CDR2 sequence identical to the VL CDR2 sequence of any one of the second antibodies listed in Table D, wherein the first and second antibodies are the same or different. In another embodiment, an antibody of the invention may have a VL CDR1 sequence identical to the VL CDR2 sequence of any one of the first antibodies listed in Table D; and a VL CDR3 sequence identical to the VL CDR3 sequence of any one of the second antibodies listed in Table D, wherein the first and second antibodies are the same or different. In another embodiment, an antibody of the invention may have a VL CDR2 sequence identical to the VL CDR2 sequence of any one of the first antibodies listed in Table D; and a VL CDR3 sequence identical to the VL CDR3 sequence of any one of the second antibodies listed in Table D, wherein the first and second antibodies are the same or different.

[0385] In yet another embodiment, an antibody of the invention may have a VL CDR1 sequence identical to the VL CDR1 sequence of any one of the first antibodies listed in Table D; a VL CDR2 sequence identical to the VL CDR2 sequence of any one of the second antibodies listed in Table D; and a VL CDR3 sequence identical to the VL CDR3 sequence of any one of the third antibodies listed in Table D, wherein the first, second, and third antibodies are the same or different (e.g., two from the same antibody and one from another antibody, or all three from different antibodies).

[0386] In some embodiments, an anti-IGSF8 antibody or antigen-binding fragment thereof of the invention (e.g., having the consensus CDR sequences described above) comprises at least one, two, or three (e.g., all three) corresponding VL CDRs of any one of the antibodies listed in Table G.

[0387] For example, in one embodiment, an antibody of the invention may have a VL CDR1 sequence identical to the VL CDR1 sequence of any one of the antibodies listed in Table G. In one embodiment, an antibody of the invention may have a VL CDR2 sequence identical to the VL CDR2 sequence of any one of the antibodies listed in Table G. In one embodiment, an antibody of the invention may have a VL CDR3 sequence identical to the VL CDR3 sequence of any one of the antibodies listed in Table G.

[0388] In another embodiment, an antibody of the invention may have a VL CDR1 sequence identical to the VL CDR1 sequence of any one of the first antibodies listed in Table G; and a VL CDR2 sequence identical to the VL CDR2 sequence of any one of the second antibodies listed in Table G, wherein the first and second antibodies are the same or different. In another embodiment, an antibody of the invention may have a VL CDR1 sequence identical to the VL CDR2 sequence of any one of the first antibodies listed in Table G; and a VL CDR3 sequence identical to the VL CDR3 sequence of any one of the second antibodies listed in Table G, wherein the first and second antibodies are the same or different. In another embodiment, an antibody of the invention may have a VL CDR2 sequence identical to the VL CDR2 sequence of any one of the first antibodies listed in Table G; and a VL CDR3 sequence identical to the VL CDR3 sequence of any one of the second antibodies listed in Table G, wherein the first and second antibodies are the same or different.

[0389] In yet another embodiment, an antibody of the invention may have a VL CDR1 sequence identical to the VL CDR1 sequence of any one of the first antibodies listed in Table G; a VL CDR2 sequence identical to the VL CDR2 sequence of any one of the second antibodies listed in Table G; and a VL CDR3 sequence identical to the VL CDR3 sequence of any one of the third antibodies listed in Table G, wherein the first, second, and third antibodies are the same or different (e.g., two from the same antibody and one from another antibody, or all three from different antibodies).

[0390] In some embodiments, the VL CDR1, VL CDR2, and / or VL CDR3 of an anti-IGSF8 antibody or antigen-binding fragment thereof of the present invention (e.g., one having the consensus CDR sequences described above) each or collectively has one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, compared to the amino acid sequence of the corresponding VL CDR1, VL CDR2, and / or VL CDR3 of any one of the antibodies listed in Table D.

[0391] In some embodiments, the VL CDR1, VL CDR2, and / or VL CDR3 of an anti-IGSF8 antibody or antigen-binding fragment thereof of the present invention (e.g., having the consensus CDR sequences described above) each or collectively has one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, compared to the amino acid sequence of the corresponding VL CDR1, VL CDR2, and / or VL CDR3 of any one of the antibodies listed in Table G.

[0392] Although it is expressly contemplated that in any of the following embodiments relating to specific antibodies defined by six CDR region sequences, VH CDR1, VH CDR2 and VH CDR3 comprise, consist essentially of or consist of the amino acid sequence of their respective recited SEQ ID NOs, and VL CDR1, VL CDR2 and VL CDR3 comprise, consist essentially of or consist of the amino acid sequence of their respective recited SEQ ID NOs, for simplicity only the following description uses the transitional phrase "comprising."

[0393] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 611, 623, and 631, respectively.

[0394] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 612, 623, and 631, respectively.

[0395] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 611, 624, and 631, respectively.

[0396] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 611, 625, and 631, respectively.

[0397] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 613, 623, and 631, respectively.

[0398] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 614, 623, and 631, respectively.

[0399] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 615, 623, and 631, respectively.

[0400] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 616, 623, and 631, respectively.

[0401] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 611, 626, and 631, respectively.

[0402] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 611, 627, and 631, respectively.

[0403] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 617, 623, and 631, respectively.

[0404] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 611, 628, and 631, respectively.

[0405] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 611, 629, and 631, respectively.

[0406] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 611, 630, and 631, respectively.

[0407] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 618, 623, and 631, respectively.

[0408] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 614, 625, and 631, respectively.

[0409] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 614, 629, and 631, respectively.

[0410] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 614, 625, and 631, respectively.

[0411] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 619, 629, and 631, respectively.

[0412] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 615, 625, and 631, respectively.

[0413] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 614, 625, and 631, respectively.

[0414] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 620, 625, and 631, respectively.

[0415] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 614, 625, and 631, respectively.

[0416] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 621, 635, and 631, respectively.

[0417] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 620, 625, and 631, respectively.

[0418] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 619, 625, and 631, respectively.

[0419] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 622, 625, and 631, respectively.

[0420] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 615, 625, and 631, respectively.

[0421] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 614, 629, and 631, respectively.

[0422] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 602, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 614, 628, and 631, respectively.

[0423] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 603, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 614, 624, and 631, respectively.

[0424] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 604, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 614, 625, and 631, respectively.

[0425] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 601, 603, and 605, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 614, 625, and 631, respectively.

[0426] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 643, 644, and 646, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 652, 653, and 655, respectively.

[0427] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 643, 644, and 646, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 652, 654, and 655, respectively.

[0428] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 643, 645, and 646, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 652, 653, and 655, respectively.

[0429] In some embodiments, the anti-IGSF8 antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 643, 645, and 646, respectively, and a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 652, 654, and 655, respectively.

[0430] Framework region (FR) Anti-IGSF antibodies or antigen-binding fragments thereof according to the present disclosure can be prepared using either the framework regions (FRs) of the amino acid sequences set forth in Table D and / or Table G, or sequences that are substantially identical (e.g., have at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to the amino acid sequences of the FRs set forth in Table D and / or Table G.

[0431] In some embodiments, the anti-IGSF8 antibody or antigen-binding fragment thereof has a heavy chain variable region (VH) comprising one, two, three, or all (i.e., four) of heavy chain framework region 1 (VH FR1), heavy chain framework region 2 (VH FR2), heavy chain framework region 3 (VH FR3), and / or heavy chain framework region 4 (VH FR4) of the corresponding heavy chain framework regions of any one of the antibodies listed in Table D or G, or VH FR1, VH FR2, VH FR3, and / or VH FR4 that comprise a sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to the corresponding VH FR amino acid sequence of any one of the antibodies described in Table D or Table G.

[0432] In some embodiments, the anti-IGSF8 antibody comprises a VH FR1 of SEQ ID NO: 606, 647 or 648, or an amino acid sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 606, 647 or 648.

[0433] In some embodiments, the anti-IGSF8 antibody comprises a VH FR2 of SEQ ID NO: 607, 649, or 650, or an amino acid sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 607, 649, or 650.

[0434] In some embodiments, the anti-IGSF8 antibody comprises a VH FR3 of SEQ ID NO: 608 or 651, or an amino acid sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 608 or 651.

[0435] In some embodiments, the anti-IGSF8 antibody comprises a VH FR4 of SEQ ID NO: 609 or 610, or an amino acid sequence substantially identical to SEQ ID NO: 609 or 610 (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity).

[0436] In some embodiments, the anti-IGSF8 antibody has a VH comprising one, two, three, or all of VH FR1, VH FR2, VH FR3, and / or VH FR4 comprising the amino acid sequence of SEQ ID NO: 606, 607, 608, and / or 609, respectively, or an amino acid sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 606, 607, 608, and / or 609.

[0437] In some embodiments, the anti-IGSF8 antibody has a VH comprising one, two, three, or all of VH FR1, VH FR2, VH FR3, and / or VH FR4 comprising the amino acid sequence of SEQ ID NO: 606, 607, 608, and / or 609, respectively, or an amino acid sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 606, 607, 608, and / or 610.

[0438] In some embodiments, the anti-IGSF8 antibody has a VH comprising one, two, three, or all of VH FR1, VH FR2, VH FR3, and / or VH FR4 comprising the amino acid sequence of SEQ ID NO: 647, 649, 651, and / or 610, respectively, or an amino acid sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 647, 649, 651, and / or 610.

[0439] In some embodiments, the anti-IGSF8 antibody has a VH comprising one, two, three, or all of VH FR1, VH FR2, VH FR3, and / or VH FR4 comprising the amino acid sequence of SEQ ID NO: 648, 649, 651, and / or 610, respectively, or an amino acid sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 648, 649, 651, and / or 610.

[0440] In some embodiments, the anti-IGSF8 antibody has a VH comprising one, two, three, or all of VH FR1, VH FR2, VH FR3, and / or VH FR4 comprising the amino acid sequence of SEQ ID NO: 648, 650, 651, and / or 610, respectively, or an amino acid sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 648, 650, 651, and / or 610.

[0441] In some embodiments, the anti-IGSF8 antibody or antigen-binding fragment thereof has a light chain variable region (VL) comprising one, two, three, or all (i.e., four) of VL FR1, VL FR2, VL FR3, and / or VL FR4 that comprise light chain framework region 1 (VL FR1), light chain framework region 2 (VL FR2), light chain framework region 3 (VL FR3), and / or light chain framework region 4 (VL FR4) of the corresponding light chain framework region of any one of the antibodies listed in Table D or G, or a sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to the corresponding VL FR amino acid sequence of any one of the antibodies described in Table D or Table G.

[0442] In some embodiments, the anti-IGSF8 antibody comprises a VL FR1 of SEQ ID NO: 632, 633, 656, or 657, or an amino acid sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 632, 633, 656, or 657.

[0443] In some embodiments, the anti-IGSF8 antibody comprises a VL FR2 of SEQ ID NO: 634, 635, 636, 637, 658, or 659, or an amino acid sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 634, 635, 636, 637, 658, or 659.

[0444] In some embodiments, the anti-IGSF8 antibody comprises a VL FR3 of SEQ ID NO: 638, 639, 640, 660, 661, 662, or 663, or an amino acid sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 638, 639, 640, 660, 661, 662, or 663.

[0445] In some embodiments, the anti-IGSF8 antibody comprises a VL FR4 of SEQ ID NO: 641, 642, 664, or 665, or an amino acid sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 641, 642, 664, or 665.

[0446] In some embodiments, the anti-IGSF8 antibody has a VL that comprises one, two, three, or all of the amino acid sequences of SEQ ID NOs: 632, 634, 638, and / or 641, respectively, or substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to SEQ ID NOs: 632, 634, 638, and / or 641.

[0447] In some embodiments, the anti-IGSF8 antibody has a VL comprising one, two, three, or all of VL FR1, VL FR2, VL FR3, and / or VL FR4 comprising the amino acid sequence of SEQ ID NO: 633, 635, 639, and / or 642, respectively, or an amino acid sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 633, 635, 639, and / or 642.

[0448] In some embodiments, the anti-IGSF8 antibody has a VL comprising one, two, three, or all of VL FR1, VL FR2, VL FR3, and / or VL FR4 comprising the amino acid sequence of SEQ ID NO: 632, 635, 639, and / or 64247, or an amino acid sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 632, 635, 639, and / or 642, respectively.

[0449] In some embodiments, the anti-IGSF8 antibody has a VL comprising one, two, three, or all of VL FR1, VL FR2, VL FR3, and / or VL FR4 comprising the amino acid sequence of SEQ ID NO: 632, 636, 639, and / or 642, respectively, or an amino acid sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 632, 636, 639, and / or 642.

[0450] In some embodiments, the anti-IGSF8 antibody has a VL comprising one, two, three, or all of VL FR1, VL FR2, VL FR3, and / or VL FR4 comprising the amino acid sequence of SEQ ID NO: 632, 637, 640, and / or 642, respectively, or an amino acid sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 632, 637, 639, and / or 642, respectively.

[0451] In some embodiments, the anti-IGSF8 antibody has a VL comprising one, two, three, or all of VL FR1, VL FR2, VL FR3, and / or VL FR4 comprising the amino acid sequence of SEQ ID NO: 656, 658, 660, and / or 664, respectively, or an amino acid sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 656, 658, 660, and / or 664.

[0452] In some embodiments, the anti-IGSF8 antibody has a VL comprising one, two, three, or all of VL FR1, VL FR2, VL FR3, and / or VL FR4 comprising the amino acid sequence of SEQ ID NO: 657, 659, 661, and / or 665, respectively, or an amino acid sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 657, 659, 661, and / or 665.

[0453] In some embodiments, the anti-IGSF8 antibody has a VL comprising one, two, three, or all of VL FR1, VL FR2, VL FR3, and / or VL FR4 comprising the amino acid sequence of SEQ ID NO: 657, 659, 662, and / or 665, respectively, or an amino acid sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 657, 659, 662, and / or 665.

[0454] In some embodiments, the anti-IGSF8 antibody has a VL comprising one, two, three, or all of VL FR1, VL FR2, VL FR3, and / or VL FR4 comprising the amino acid sequence of SEQ ID NO: 657, 659, 663, and / or 665, respectively, or an amino acid sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 657, 659, 663, and / or 665.

[0455] In some embodiments, the monoclonal antibody or antigen-binding fragment thereof is a human-mouse chimeric antibody, a humanized antibody, a CDR-grafted antibody, or a resurfaced antibody.

[0456] In some embodiments, the antigen-binding fragment is a Fab, Fab', F(ab'), F d , single-chain Fv or scFv, disulfide-linked F v , V-NAR domain, IgNar, intrabody, IgGΔCH2, minibody, F(ab')3, tetrabody, triabody, diabody, single domain antibody, DVD-Ig, Fcab, mAb2, (scFv)2, or scFv-FC.

[0457] In some embodiments, the monoclonal antibody or antigen-binding fragment thereof has a K of less than about 25 nM, 20 nM, 15 nM, 10 nM, 5 nM, 2 nM, or 1 nM. d It binds to IGSF8.

[0458] In some embodiments, the antibody binds to IGSF8 from multiple species, for example, in some embodiments, the antibody binds to human IGSF8 and also binds to IGSF8 from at least one non-human mammal selected from mouse, rat, dog, guinea pig, and cynomolgus monkey.

[0459] In some embodiments, multispecific antibodies are provided. In some embodiments, bispecific antibodies are provided. Non-limiting exemplary bispecific antibodies include antibodies comprising a first arm comprising a heavy chain / light chain combination that binds to a first antigen and a second arm comprising a heavy chain / light chain combination that binds to a second antigen. Further non-limiting exemplary multispecific antibodies are dual variable domain antibodies. In some embodiments, the bispecific antibody comprises a first arm that inhibits binding of IGSF8 and a second arm that stimulates T cells, for example, by binding to CD3.

[0460] Another aspect of the present invention provides a monoclonal antibody or antigen-binding fragment thereof that competes with the above-described monoclonal antibody or antigen-binding fragment thereof of the present invention.

[0461] In certain embodiments, the antibody or antigen-binding portion / fragment thereof preferably has a K of 5 nM or less, 2 nM or less, or 1 nM or less. D It specifically binds to the D1 ECD (or Ig-V set domain) of IGSF8.

[0462] In certain embodiments, the antibody or antigen-binding portion / fragment thereof inhibits binding of IGSF8 to KIR3DL1 / 2.

[0463] In certain embodiments, the antibody or antigen-binding portion / fragment thereof inhibits binding of IGSF8 to the D2 domain of KIR3DL1 / 2, for example, to an epitope comprising S165, I171, and / or M186 of KIR3DL1 / 2.

[0464] Another aspect of the present invention provides a monoclonal antibody or antigen-binding portion / fragment thereof that specifically binds to the D1 ECD (or Ig-V set domain) of IGSF8 and inhibits binding to KIR3DL1 / 2, for example, binding to the D2 domain of KIR3DL1 / 2 (e.g., an epitope including S165, I171, and / or M186 of KIR3DL1 / 2).

[0465] In some embodiments, the monoclonal antibody or antigen-binding portion / fragment thereof has a K of 5 nM or less, 2 nM or less, or 1 nM or less. D It has.

[0466] In a related aspect, the present invention also provides polynucleotides encoding the monoclonal antibodies of the present invention, their heavy or light chains, or antigen-binding portions / fragments thereof. See separate sections below.

[0467] In a related aspect, the present invention also provides polynucleotides that hybridize under stringent conditions to the polynucleotides of the present invention, or their complements.

[0468] In a related aspect, the present invention also provides a vector comprising a polynucleotide of the invention, see separate section below.

[0469] In a related aspect, the present invention also provides a host cell comprising a polynucleotide of the invention, or a vector of the invention, for expressing the encoded monoclonal antibody, its heavy or light chain, or antigen-binding portion / fragment thereof. See separate section below.

[0470] In a related aspect, the present invention also provides a method for producing a monoclonal antibody of the present invention, its heavy or light chain, or antigen-binding site / fragment thereof, comprising the steps of: (i) culturing a host cell of the present invention capable of expressing said monoclonal antibody, its heavy or light chain, or antigen-binding site / fragment thereof under conditions suitable for expressing said monoclonal antibody, its heavy or light chain, or antigen-binding site / fragment thereof; and (ii) recovering / isolating / purifying the expressed monoclonal antibody, its heavy or light chain, or antigen-binding site / fragment thereof.

[0471] In a related aspect, the present invention also provides a device or kit comprising at least one antibody, monoclonal antibody, heavy chain or light chain thereof, or antigen-binding site / fragment thereof of the present invention, and optionally a label for detecting at least one of said antibody, monoclonal antibody, heavy chain or light chain, or antigen-binding site / fragment thereof, or a complex comprising at least one of said antibody, monoclonal antibody, heavy chain or light chain, or antigen-binding site / fragment thereof.

[0472] Anti-IGSF8 antibodies according to the present disclosure can be prepared using any of the antibody sequences set forth herein (e.g., variable domain amino acid sequences, variable domain amino acid sequence pairs, CDR amino acid sequences, variable domain CDR amino acid sequence sets, variable domain CDR amino acid sequence set pairs, and / or framework region amino acid sequences), any of which can be prepared, for example, as a monoclonal antibody, multispecific antibody, chimeric antibody, antibody mimetic, scFv, or antibody fragment.

[0473] KIR3DL1 / 2 antibody One aspect of the present invention provides a monoclonal antibody specific to KIR3DL1 / 2. In certain embodiments, the monoclonal antibody is specific to the extracellular domain (ECD) of KIR3DL1 / 2. In certain embodiments, the monoclonal antibody is specific to the second Ig-like extracellular domain (D2 domain) of KIR3DL1 / 2, which is involved in IGSF8 binding. In some embodiments, an antibody that blocks binding to IGSF8 is provided. In certain embodiments, the anti-KIR3DL1 / 2 monoclonal antibody inhibits binding of IGSF8 to KIR3DL2 and / or KIR3DL1, for example, inhibits binding of IGSF8 to residues S165, I171, and / or M186 of KIR3DL1 / 2.

[0474] In certain embodiments, the monoclonal antibody is specific to human KIR3DL1 / 2. In some embodiments, the anti-KIR3DL1 / 2 antibody inhibits signal transduction mediated by IGSF8 via KIR3DL1 / 2. In certain embodiments, the monoclonal antibody competes with any one of the anti-KIR3DL1 / 2 antibodies for binding to IGSF8.

[0475] In certain embodiments, the anti-KIR3DL1 / 2 antibody is a human-mouse chimeric antibody, a humanized antibody, a human antibody, a CDR-grafted antibody, or a resurfaced antibody.

[0476] In certain embodiments, the antigen-binding fragment is a Fab, Fab', F(ab'), F d , single chain Fv or scFv, disulfide-linked F v , V-NAR domain, IgNar, intrabody, IgGΔCH2, minibody, F(ab')3, tetrabody, triabody, diabody, single domain antibody, DVD-Ig, Fcab, mAb2, (scFv)2, or scFv-Fc.

[0477] In certain embodiments, the monoclonal antibody or antigen-binding fragment thereof has a K of less than about 25 nM, less than 20 nM, less than 15 nM, less than 10 nM, less than 5 nM, less than 2 nM, or less than 1 nM. d It binds to KIR3DL1 / 2.

[0478] A related embodiment provides a monoclonal antibody or antigen-binding fragment thereof that competes with a monoclonal antibody or antigen-binding fragment thereof of the invention for binding to KIR3DL1 / 2.

[0479] In certain embodiments, the antibody or antigen-binding portion / fragment thereof binds to the second / intermediate / D2 ECD of KIR3DL1 / 2 with a K of preferably 5 nM or less, 2 nM or less, or 1 nM or less. D It specifically binds to

[0480] In certain embodiments, the antibody or antigen-binding portion / fragment thereof inhibits binding of IGSF8 to KIR3DL1 / 2.

[0481] Another aspect of the present invention provides a monoclonal antibody or antigen-binding portion / fragment thereof that specifically binds to the middle / D2 ECD of KIR3DL1 / 2 (e.g., specifically binds to an epitope comprising residues S165, I171, and / or M186), and inhibits binding of IGSF8 to KIR3DL1 / 2.

[0482] In certain embodiments, the monoclonal antibody or antigen-binding portion / fragment thereof has a K of 5 nM or less, 2 nM or less, or 1 nM or less. D It has.

[0483] 7. Humanized antibodies In some embodiments, the IGSF8 antibody is a humanized antibody, which is useful as a therapeutic molecule to reduce or eliminate human immune responses to non-human antibodies (e.g., human anti-mouse antibody (HAMA) responses), which can result in an immune response to antibody therapeutics and reduce the effectiveness of the therapeutic.

[0484] Antibody can be humanized by standard method.Non-limiting exemplary method of humanization includes, for example, the method described in U.S. Patent No. 5,530,101; 5,585,089; 5,693,761; 5,693,762; 6,180,370; Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-27 (1988); Verhoeyen et al., Science 239:1534-36 (1988); and U.S. Patent Publication No. 2009 / 0136500, all of which are incorporated by reference.

[0485] A humanized antibody is an antibody in which at least one amino acid in a framework region of a non-human variable region is substituted with an amino acid at the corresponding position in a human framework region, hi some embodiments, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least 11, at least 12, at least 15, or at least 20 amino acids in the framework regions of the non-human variable region are substituted with an amino acid from one or more corresponding positions in one or more human framework regions.

[0486] In some embodiments, some of the corresponding human amino acids used for substitutions are derived from framework regions of different human immunoglobulin genes. That is, in some such embodiments, one or more of the non-human amino acids may be substituted with corresponding amino acids from the human framework region of a first human antibody or encoded by a first human immunoglobulin gene, one or more of the non-human amino acids may be substituted with corresponding amino acids from the human framework region of a second human antibody or encoded by a second human immunoglobulin gene, and one or more of the non-human amino acids may be substituted with corresponding amino acids from the human framework region of a third human antibody or encoded by a third human immunoglobulin gene. Furthermore, in some embodiments, all of the corresponding human amino acids used for substitutions in a single framework region, e.g., FR2, need not be derived from the same human framework. However, in some embodiments, all of the corresponding human amino acids used for substitutions are derived from the same human antibody or encoded by the same human immunoglobulin gene.

[0487] In some embodiments, antibodies are humanized by replacing one or more entire framework regions with corresponding human framework regions. In some embodiments, the human framework region having the highest level of homology to the non-human framework region being replaced is selected. In some embodiments, such a humanized antibody is a CDR-grafted antibody.

[0488] In some embodiments, following CDR grafting, one or more framework amino acids are reverted to the corresponding amino acids in the mouse framework regions. Such "backmutations" are made in some embodiments to retain one or more mouse framework amino acids that are likely to contribute to the structure of one or more CDRs and / or that may be involved in antigen contact and / or that are likely to be involved in the overall structural integrity of the antibody. In some embodiments, no more than 10, no more than 9, no more than 8, no more than 7, no more than 6, no more than 5, no more than 4, no more than 3, no more than 2, no more than 1, or no mutations are made in the framework regions of the antibody after CDR grafting.

[0489] In some embodiments, a humanized antibody also comprises a human heavy chain constant region and / or a human light chain constant region.

[0490] 8. Chimeric antibodies In some embodiments, the IGSF8 antibody is a chimeric antibody. In some embodiments, the IGSF8 antibody comprises at least one non-human variable region and at least one human constant region. In some such embodiments, all of the variable regions of the IGSF8 antibody are non-human variable regions, and all of the constant regions of the IGSF8 antibody are human constant regions. In some embodiments, one or more variable regions of the chimeric antibody are murine variable regions. The human constant region of the chimeric antibody need not be of the same isotype as the non-human constant region, if any, that it replaces. Chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA 81:6851-55 (1984).

[0491] 9. Human antibodies In some embodiments, the IGSF8 antibody is a human antibody. Human antibodies can be produced by any suitable method. A non-routine exemplary method includes producing human antibodies in transgenic mice containing human immunoglobulin loci. See, for example, Jakobovits et al., Proc. Natl. Acad. Sci. USA 90:2551-55 (1993); Jakobovits et al., Nature 362:255-8 (1993); Onberg et al., Nature 368:856-9 (1994); and U.S. Patent Nos. 5,545,807; 6,713,610; 6,673,986; 6,162,963; 5,545,807; 6,300,129; 6,255,458; 5,877,397; 5,874,299; and 5,545,806.

[0492] Non-limiting exemplary methods include producing human antibodies using phage display libraries. See, e.g., Hoogenboom et al., J. Mol. Biol. 227:381-8 (1992); Marks et al., J. Mol. Biol. 222:581-97 (1991); and PCT Publication WO 99 / 10494.

[0493] Human antibody constant region In some embodiments, the humanized, chimeric, or human antibodies described herein comprise one or more human constant regions. In some embodiments, the human heavy chain constant region is an isotype selected from IgA, IgG, and IgD. In some embodiments, the human light chain constant region is an isotype selected from K and λ. In some embodiments, the antibodies described herein comprise a human IgG constant region, e.g., human IgG1, IgG2, IgG3, or IgG4. In some embodiments, the antibody or Fc fusion partner comprises, for example, a C237S mutation in the IgG1 constant region. In some embodiments, the antibodies described herein comprise a human IgG2 heavy chain constant region. In some such embodiments, the IgG2 constant region comprises a P331S mutation, as described in U.S. Patent No. 6,900,292. In some embodiments, the antibodies described herein comprise a human IgG4 heavy chain constant region. In some such embodiments, the antibodies described herein comprise a S241P mutation in the human IgG4 constant region. See, for example, Angal et al., Mol. Immunol. 30(1):105-108 (1993). In some embodiments, the antibodies described herein comprise a human IgG4 constant region and a human kappa light chain.

[0494] The choice of heavy chain constant region can determine whether an antibody has effector function in vivo. In some embodiments, such effector function can include antibody-dependent cell-mediated cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC) and / or antibody-dependent cellular phagocytosis (ADCP), which can result in killing of cells to which the antibody binds. Typically, antibodies containing human IgG1 or IgG3 heavy chains have effector function.

[0495] In some embodiments, effector function is undesirable. For example, in some embodiments, effector function may be undesirable in the treatment of inflammatory conditions and / or autoimmune diseases. In some such embodiments, a human IgG4 or IgG2 heavy chain constant region is selected or engineered. In some embodiments, the IgG4 constant region comprises the S241P mutation.

[0496] In some other embodiments, effector function may be undesirable if the purpose of the antibody is to block receptor-ligand interaction, but depletion of target cells is undesirable. In some such embodiments, a heavy chain constant region is selected or engineered to have an Fc lacking effector function. Non-limiting examples of Fc with reduced effector function and mutations that confer reduced effector function to Fc are described, for example, in Liu et al., Antibodies 9:64 (2020), the entire contents of which are incorporated herein by reference.

[0497] In some embodiments, the mutation that confers reduced effector function is an L234A / L235A mutation in the C1q binding site. In some embodiments, the heavy chain constant region with reduced effector function is a human IgG1 or IgG4 that contains the L234A / L235A mutation, also known as IgG1-L234A / L235A (IgG1-LALA) or IgG4-L234A / L235A (IgG4-LALA), respectively.

[0498] In some embodiments, the mutation that confers reduced effector function is a P329G mutation, which can disrupt the interaction between human IgG and human FcγR. In some embodiments, the mutation that confers reduced effector function is L234A / L235A / P329G. In some embodiments, the heavy chain constant region with reduced effector function is a human IgG1 comprising the L234A / L235A / P329G mutations, also known as IgG1-L234A / L235A / P329G (IgG1-LALA-PG).

[0499] In some embodiments, the mutation that confers reduced effector function is an N297A, N297Q, or N297G mutation, which removes the glycan central to binding between human IgG and C1q and FcγR. In some embodiments, the heavy chain constant region with reduced effector function is a human IgG1 containing an N297A, N297Q, or N297G mutation, also known as IgG1-N297A / Q / G (IgG1-NA).

[0500] In some embodiments, the mutations that confer reduced effector function are L235A / G237A / E318A mutations. In some embodiments, the heavy chain constant region with reduced effector function is a human IgG1 containing the L235A / G237A / E318A mutations, also known as IgG1-L235A / G237A / E318A (IgG1-AAA).

[0501] In some embodiments, the mutation that confers reduced effector function is G236R / L328R, which can result in reduced or completely abolished binding to multiple FcγRs. In some embodiments, the heavy chain constant region with reduced effector function is a human IgG1 containing the G236R / L328R mutation, also known as IgG1-G236R / L328R (IgG1-RR).

[0502] In some embodiments, the mutation that confers reduced effector function is a S298G / T299A mutation, which can abolish or significantly reduce binding to C1q and most FcγRs. In some embodiments, the heavy chain constant region with reduced effector function is an IgG1 containing the S298G / T299A mutation, also known as IgG1-S298G / T299A (IgG1-GA).

[0503] In some embodiments, the mutations that confer reduced effector function are L234F / L235E / P331S mutations, which can result in reduced binding to low affinity FcγRs and undetectable binding to FcγRI. In some embodiments, the heavy chain constant region with reduced effector function is a human IgG1 containing the L234F / L235E / P331S mutations, also known as IgG1-L234F / L235E / P331S (IgG1-FES).

[0504] In some embodiments, the mutations that confer reduced effector function are L234F / L235E / D265A mutations, which can result in potent silencing of the Fc region. In some embodiments, the heavy chain constant region with reduced effector function is a human IgG1 containing the L234F / L235E / D265A mutations, also known as IgG1-L234F / L235E / D265A (IgG1-FEA).

[0505] In some embodiments, the mutations that confer reduced effector function are E233P / L234V / L235A / G236del / S267K mutations, which may result in the loss of binding to multiple FcγRs. In some embodiments, the heavy chain constant region with reduced effector function is a human IgG1 comprising the E233P / L234V / L235A / G236del / S267K mutations, also known as IgG1--E233P / L234V / L235A / G236del / S267K.

[0506] In some embodiments, the mutations that confer reduced effector function are 228P / L235E mutations that prevent F9ab arm exchange in human IgG4. In some embodiments, the heavy chain constant region with reduced effector function is human IgG4 comprising the 228P / L235E mutations, also known as IgG4-S228P / L235E (IgG4-PE).

[0507] In some embodiments, the mutations that confer reduced effector function are H268Q / V309L / A30S / P331S mutations. In some embodiments, the heavy chain constant region with reduced effector function is a human IgG2 containing the H268Q / V309L / A30S / P331S mutations, also known as IgG2-H268Q / V309L / A30S / P331S (IgG2m4).

[0508] In some embodiments, the mutations that confer reduced effector function are V234A / G237A / P238S / H268A / V309L / A330S / P331S mutations. In some embodiments, the heavy chain constant region with reduced effector function is a human IgG2 containing the V234A / G237A / P238S / H268A / V309L / A330S / P331S mutations, also known as IgG2-V234A / G237A / P238S / H268A / V309L / A330S / P331S (IgG2c4d).

[0509] Any antibody described herein can be purified by any suitable method. Such methods include, but are not limited to, the use of affinity matrix or hydrophobic interaction chromatography. Suitable affinity ligands include ligands that bind to the antigen and / or epitope to which the antibody binds, as well as ligands that bind to the antibody constant region. For example, Protein A, Protein G, Protein A / G, or an antibody affinity column can be used to bind the constant region and purify the antibody.

[0510] In some embodiments, hydrophobic interaction chromatography (HIC), e.g., on a butyl or phenyl column, has also been used to purify some polypeptides. Many methods for purifying polypeptides are known in the art.

[0511] Alternatively, in some embodiments, the antibodies described herein are produced in a cell-free system. Non-limiting exemplary cell-free systems are described, for example, in Sitaraman et al., Methods Mol. Biol. 498:229-44 (2009); Sprin, Trends Biotechnol. 22:538-45 (2004); Endo et al., Biotechnol. Adv. 21:695-713 (2003).

[0512] 10. Antibody Characteristics In some embodiments, the subject IGSF8 antibodies bind to IGSF8 and inhibit IGSF8-mediated signaling, e.g., upregulation or downregulation of downstream genes as shown in Figures 4 and 5A-5D. In some embodiments, the IGSF8 antibodies have a binding affinity (K D ) or EC50 value. In some embodiments, the extent of binding of an IGSF8 antibody to an unrelated, non-IGSF8 protein is less than about 10% of the binding of the antibody to IGSF8, as measured, for example, by radioimmunoassay (RIA). In some embodiments, the IGSF8 antibody binds to an epitope of IGSF8 that is conserved among IGSF8 from different species. In some embodiments, the IGSF8 antibody binds to the same epitope as a human or humanized IGSF8 antibody that binds to humIGSF8. In some embodiments, the IGSF8 antibody is conjugated to a label, which is a moiety that facilitates detection of the antibody and / or the molecule to which the antibody binds. Non-limiting exemplary labels include, but are not limited to, radioisotopes, fluorescent groups, enzyme groups, chemiluminescent groups, biotin, epitope tags, metal-binding tags, etc. Those skilled in the art can select an appropriate label depending on the intended use.

[0513] In some embodiments, the label is conjugated to the antibody using in vitro chemical methods. Non-limiting exemplary chemical methods of conjugation are known in the art and include commercially available services, methods, and / or reagents from, for example, Thermo Scientific Life Science Research Produces (formerly Pierce; Rockford, IL), Prozyme (Hayward, CA), SACRI Antibody Services (Calgary, Canada), AbD Serotec (Raleigh, NC), etc. In some embodiments, when the label is a polypeptide, the label can be expressed from the same expression vector as at least one antibody chain to produce a polypeptide comprising the label fused to the antibody chain.

[0514] 11.IGSF8 ECD, Fusion, and Small Peptides In some embodiments, the IGSF8 antagonist is an IGSF8 polypeptide, such as full-length IGSF8 or a fragment thereof that inhibits binding of IGSF8 to its ligand.

[0515] In some embodiments, the IGSF8 fragment is the IGSF8 extracellular domain (ECD). In some embodiments, the IGSF8 fragment is a full-length IGSF8 ECD. In certain embodiments, the ECD functions as an antagonistic polypeptide that inhibits the function of an IGSF8 receptor, such as KIR3dL1 / 2, resulting from wild-type IGSF8 binding. However, in other embodiments, the ECD functions as an agonist polypeptide that functions similarly to wild-type full-length IGSF8 on its receptor, such as KIR3DL1 / 2.

[0516] In some embodiments, the invention provides IGSF8 ECD fragments that comprise, for example, at least 80%, at least 85%, at least 90%, or at least 95% of the full-length IGSF8 ECD amino acid sequence from which it is derived. In some embodiments, the IGSF8 ECD fragment comprises, consists essentially of, or consists of the D1 (or most of the N-terminal Ig-V set) domain of IGSF8.

[0517] In some embodiments, the invention provides IGSF8 ECD variants that comprise, for example, at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, at least 98%, or at least 99% sequence identity to the full-length IGSF8 ECD or fragment (e.g., the Ig-V set D1 domain) from which it is derived. In some embodiments, the variants retain the ability to bind KIR3DL1 / 2.

[0518] In other embodiments, the IGSF8 ECD is derived from a non-human IGSF8 ECD and may be either full-length, a fragment (e.g., the D1 or Ig-V set domain), or a variant (e.g., having at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, at least 98%, or at least 99% sequence identity and retaining the ability to bind KIR3DL1 / 2).

[0519] In a related embodiment, the present invention provides IGSF8 variants that lack the D2-D4 Ig-like C2 domains of the ECD but retain the D1 Ig-V set domain of the ECD, and such variants can substantially retain the functions of wt IGSF8, such as KIR3DL1 / 2 binding ability.

[0520] In some embodiments, IGSF8 or an IGSF8 fragment or an IGSF8 variant is combined with at least one fusion partner.

[0521] Thus, in some such embodiments, the invention provides a fusion of full-length IGSF8, such as a C-terminal fusion, with an Ig Fc region. In one embodiment, the Ig Fc fusion is a human IgG1 Fc fusion.

[0522] The present invention further provides a full-length IGSF8 ECD and a...

Claims

1. 1. An isolated or recombinant monoclonal antibody specific for IGSF8, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, and a light chain variable region (VL) comprising a VL CDR1, a VL CDR2, and a VL CDR3: (1) the VH CDR1, VH CDR2, and VH CDR3 comprise, consist essentially of, or consist of the VH CDR1, VH CDR2, and VH CDR1, respectively, of antibody L1-23; and (2) the VL CDR1, VL CDR2, and VL CDR3 comprise, consist essentially of, or consist of the VL CDR1, VL CDR2, and VL CDR3, respectively, of antibody L1-23; wherein the heavy chain constant region has an Fc domain that is deficient in antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and / or antibody-dependent cellular phagocytosis (ADCP), and the Fc domain comprises L234A / L235A mutations; The monoclonal antibody.

2. (1) VH CDR1, VH CDR2, and VH CDR3 comprise, consist essentially of, or consist of GFTFSTYG (SEQ ID NO: 601), IWDDGSYK (SEQ ID NO: 602), and ARDGSGWGYAFDI (SEQ ID NO: 605), respectively; and (2) VL CDR1, VL CDR2, and VL CDR3 comprise, consist essentially of, or consist of QDIGPW (SEQ ID NO: 614), GSP (SEQ ID NO: 625), and QQYDSFPYT (SEQ ID NO: 631), respectively; The monoclonal antibody of claim 1.

3. (1) VH is QVQLVESGGGVVQPGRSLRLSCAAS (SEQ ID NO: 606), or an amino acid sequence having at most 1, 2, 3, 4, or 5 substitutions, deletions, and / or additions thereof, MHWVRQAPGKGLEWVAV (SEQ ID NO: 607), or an amino acid sequence having at most 1, 2, 3, 4, or 5 substitutions, deletions, and / or additions thereof, YYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC (SEQ ID NO: 608), or an amino acid sequence having at most 1, 2, 3, 4, or 5 substitutions, deletions, and / or additions thereof, and WGQGTLVTVSS (SEQ ID NO: 610), or an amino acid sequence having at most 1, 2, 3, 4, or 5 substitutions, deletions, and / or additions thereof. VH FR1, VH FR2, VH FR3 and / or VH FR4; and (2) VL comprises an amino acid sequence having at most 1, 2, 3, 4, or 5 substitutions, deletions, and / or additions thereof, such as DIQLTQSPSSLSASVGDRVTITCQAS (SEQ ID NO: 632), or an amino acid sequence having at most 1, 2, 3, 4, or 5 substitutions, deletions, and / or additions thereof, LNWYQHKPGKAPKPLVF (SEQ ID NO: 637), or an amino acid sequence having at most 1, 2, 3, 4, or 5 substitutions, deletions, and / or additions thereof, NLETGVPSRFSASGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 640), or an amino acid sequence having at most 1, 2, 3, 4, or 5 substitutions, deletions, and / or additions thereof, and FGQGTKVEIK (SEQ ID NO: 642), or an amino acid sequence having at most 1, 2, 3, 4, or 5 substitutions, deletions, and / or additions thereof, respectively. VL FR2, VL FR3 and / or VL FR4, The monoclonal antibody of claim 1.

4. (1) the VH comprises the amino acid sequence of the VH sequence of antibody L1-23 (SEQ ID NO:670), or an amino acid sequence having the same VH CDR sequence and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity in the framework regions of SEQ ID NO:670; and (2) VH comprises the amino acid sequence of the VL sequence of antibody L1-23 (SEQ ID NO: 694), or an amino acid sequence having the same VH CDR sequence and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity in the framework regions of SEQ ID NO: 694; The monoclonal antibody of claim 1.

5. The monoclonal antibody of claim 1, wherein the VH and VL sequences comprise the amino acid sequences of SEQ ID NOs: 670 and 694, respectively.

6. 2. The monoclonal antibody of claim 1, which is a human-mouse chimeric antibody, a humanized antibody, a human antibody, a CDR-grafted antibody, or a resurfaced antibody.

7. 2. The monoclonal antibody of claim 1, wherein the heavy chain constant region having a deleted Fc domain is selected from the group consisting of IgG1-L234A / L235A (IgG1-LALA), IgG1-L234A / L235A / P329G (IgG1-LALA-PG), and IgG4-L234A / L235A (IgG4-LALA).

8. The monoclonal antibody or antigen-binding fragment thereof has a K of less than about 25 nM, less than 20 nM, less than 15 nM, less than 10 nM, less than 5 nM, less than 2 nM, or less than 1 nM. ｄ The monoclonal antibody of claim 1, which binds to IGSF8 at

9. A polynucleotide encoding the monoclonal antibody of any one of claims 1 to 8, or the heavy or light chain thereof.

10. A vector comprising the polynucleotide of claim 9.

11. A host cell comprising the polynucleotide of claim 9 for expressing the encoded monoclonal antibody, or a heavy or light chain thereof.

12. A method for producing the monoclonal antibody according to any one of claims 1 to 8, or its heavy chain or light chain, comprising: (i) culturing a host cell capable of expressing said monoclonal antibody, or its heavy or light chain, under conditions suitable for expression of said monoclonal antibody, or its heavy or light chain; and, optionally, (ii) recovering / isolating / purifying the expressed monoclonal antibody, or its heavy or light chain; The method.

13. An anti-IGSF8 monoclonal antibody according to any one of claims 1 to 8 for use in modulating an immune response in a subject in need thereof or for treating cancer in a subject in need thereof.

14. The anti-IGSF8 monoclonal antibody of claim 13, which is conjugated to a cytotoxic substance.

15. Cancers include melanoma (including cutaneous melanoma), cervical cancer, lung cancer (e.g., non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma), colorectal cancer (including colon cancer and colon adenocarcinoma), lymphoma (including B-cell lymphoma and diffuse large B-cell lymphoma (DLBCL)), leukemia (including chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML)), bladder cancer (BLCA), breast cancer, head and neck cancer, head and neck squamous cell carcinoma, thyroid cancer, urothelial carcinoma, The anti-IGSF8 monoclonal antibody of claim 13, which is selected from the group consisting of uterine cancer (including endometrial cancer, uterine cancer and uterine corpus endometrial cancer (UCEC)), esophageal cancer, liver cancer, cancer of the ganglia, kidney cancer, pancreatic cancer, pancreatic ductal carcinoma, ovarian cancer, prostate cancer, gastric cancer, ovarian cancer, glioma, glioblastoma, neuroblastoma, thymoma, cholangiocarcinoma, soft tissue sarcoma, T-cell lymphoma, B-CLL, and cancer infiltrated by immune cells expressing receptors for IGSF8.

16. The anti-IGSF8 monoclonal antibody of claim 13, wherein cancer cells and / or tumor immune infiltrating cells in the subject express IGSF8.

17. The anti-IGSF8 monoclonal antibody according to claim 13, wherein the anti-IGSF8 monoclonal antibody or antigen-binding fragment thereof stimulates the activation and / or infiltration of T cells and / or NK cells into the tumor microenvironment.

18. The anti-IGSF8 monoclonal antibody of claim 13, wherein the use further comprises administering to the subject an effective amount of a second therapeutic agent comprising immunotherapy, an immune checkpoint inhibitor, a cancer vaccine, a chimeric antigen receptor, a chemotherapeutic agent, radiation therapy, an anti-angiogenic agent, a growth inhibitor, an immuno-oncology agent, an anti-neoplastic composition, surgery, or a combination thereof.

19. The anti-IGSF8 monoclonal antibody of claim 18, (i) the immune checkpoint inhibitor is an antibody or antigen-binding fragment thereof specific for PD-1, PD-L1, PD-L2, LAG3, TIGIT, TIM3, NKG2A, CD276, VTCN1, VISR, or HHLA2; (ii) the immune checkpoint inhibitor is an anti-PD-1 antibody, such as cemiplimab, nivolumab, or pembrolizumab; (iii) the immune checkpoint inhibitor is an anti-PD-L1 antibody, such as avelumab, durvalumab, atezolizumab, KN035, or CK-301; (iv) the immune checkpoint inhibitor is a (non-antibody) peptide inhibitor of PD-1 / PD-L1, e.g., AUNP12; a small molecule inhibitor of PD-L1, e.g., CA-170, or a macrocyclic peptide, e.g., BMS-986189; (v) The second therapeutic agent is an antibody or antigen-binding portion / fragment thereof effective in treating cancer, such as 3F8, 8H9, abagovomab, abciximab, abituzumab, abrezekimab, abrilumab, actoxumab, adalimumab, adecatumumab, aducanumab, afacevicumab, afelimomab, alacizumab pegol, alemtuzumab, alirocumab, altumomab pentetate, amatuximab, amivantamab, anatumomab mafenatox, andecaliximab, anetumab ravtansine, anifrolumab, anrukinzumab, apolizumab, Mab, apultumab ixadotin, arcitumomab, asclinicalvacuumab, acelizumab, atezolizumab, atidortoxumab, atinumab, atorolimumab, avelumab, azintuximab vedotin, bapineuzumab, basiliximab, bavituximab, BCD-100, bectumomab, begelomab, belantamab mafodotin, belimumab, bemarituzumab, benralizumab, berlimatoxumab, bermekimab, bersanlimab, bertilimumab, besilesomab, bevacizumab, bezlotoxumab, biciromab, bimagrumab, bimekizumab, bili Tamimab, bivatuzumab, bleselumab, blinatumomab, brontuzumab, brosozumab, bococizumab, brazikumab, brentuximab vedotin, briakinumab, brodalumab, brolucizumab, brontiximab, burosumab, cabilalizumab, camidanlumab tesirin, camrelizumab, canakinumab, cantuzumab mertansine, cantuzumab mertansine, caplacizumab, capromab, carlumab, carotuximab, catumaxomab, cBR-doxorubicin immunoconjugate, cedelizumab, cemiplimab, sergituzumab Munaleukin, certolizumab pegol, cetrelimab, cetuximab, civisatamab, cirumtuzumab, sitatuzumab bogatox, cixutumumab, clazakizumab, clenoliximab, clivatuzumab tetraxetan, codrituzumab, cofetuzumab peridotin, coltuximab ravtansine, conatumumab, concizumab, cosfrobiximab, crenezumab, crizanlizumab, clotedumab, CR6261, cusatuzumab, dacetuzumab, daclizumab, dalotuzumab, dapirolizumab pegol, daratumumab, dectrecumab, demcizumab,Denintuzumab mafodotin, denosumab, depatuxizumab mafodotin, dellotuximab biotin, detumomab, dezamizumab, dinutuximab, ziridabumab, domagrozumab, dorlimomab alitox, dostarlimab, drozitumab, DS-8201, durigotuzumab, dupilumab, durvalumab, dusigitumab, duvortuxizumab, ecromeximab, eculizumab, edovacomab, edrecolomab, efalizumab, efangumab, eldelumab, elezanumab, elgemtumab, elotuzumab, ersilimomab, emactuzumab Mab, emapalumab, emibetuzumab, emicizumab, enapotamab vedotin, enavatuzumab, enfortumab vedotin, enlimomab pegol, enoblitzumab, enokizumab, enoticumab, ensituximab, epitumomab cituxetan, epratuzumab, eptinezumab, erenumab, erlizumab, ertumaxomab, etaracizumab, etigilimab, etrolizumab, evinacumab, evolocumab, exbivirumab, fanolesomab, faralimomab, faricimab, farletuzumab, fasinumab, FBTA05, felvizumab, Fezakinumab, Fivatuzumab, Ficlatuzumab, Figitumumab, Filibumab, Framvotumab, Fretikumab, Flotetuzumab, Fontolizumab, Foralumab, Foravirumab, Fremanezumab, Fresolimumab, Flobocimab, Furnevetomab, Furlanumab, Futuximab, Galcanezumab, Galiximab, Gancotamab, Ganitumab, Gantenerumab, Gatipotuzumab, Gavirimomab, Gedivumab, Gemtuzumab ozogamicin, Gevokizumab, Dilvetumab, Dimcirumab, Dilentuximab, Glenvatinib ... Mab, gomiliximab, goslanemab, guselkumab, ranalumab, ibalizumab, IBI308, ibritumomab tiuxetan, icrucumab, idarucizumab, ifavotuzumab, igovomab, iradatuzumab vedotin, IMAB363, imalumab, imaprelimab, imciromab, imgatuzumab, inlacumab, indatuximab vedotin, inebilizumab, infliximab, intetumumab, inolimomab, inotuzumab ozogamicin, ipilimumab, Iomab-B, iratumumab, isatuximab,Iscalimab, istiratumab, itolizumab, ixekizumab, keliximab, labetuzumab, lacunotuzumab, radiratuzumab vedotin, lampalizumab, lanadelumab, landgrozumab, laprituximab emtansine, ralcabiximab, lebrikizumab, remaresomab, lendalizumab, lembervimab, lenzilumab, lerdelimumab, leronlimab, lesofabumab, letolizumab, lexatumumab, ribivirumab, rifastuzumab vedotin, ligelizumab, loncastuximab tesirin, rosatuximab vedotin, rilotomab Tetraxetan, lintuzumab, lirilumab, roderucizumab, lokivetumab, lorvotuzumab mertansine, lucatumumab, lurizumab pegol, rumiliximab, lumletuzumab, rupartumab, rupartumab amadotin, rutikizumab, mapatumumab, marjetuximab, marstacimab, maslimomab, mavrilimumab, matuzumab, mepolizumab, metelimumab, milatuzumab, minletumomab, mirikizumab, mirvetuximab soravtansine, mitumomab, modotuximab, mogamulizumab, monalizumab, morolimumab, mosunetuzumab , motavizumab, moxetumomab pasudotox, muromonab-CD3, nacolomab butafenatox, namilumab, naptumomab estafenatox, naratuximab emtansine, narutumab, natalizumab, nabicixizumab, navivumab, naxitamab, nebacumab, necitumumab, nemolizumab, NEOD001, nerelimomab, nesbacumab, netakimab, nimotuzumab, nirsevimab, nivolumab, nofetumomab merpentane, obilutoxaximab, obinutuzumab, ocralizumab, ocrelizumab, odulimomab, ofatumumab , olaratumab, oleculumab, orendalizumab, olokizumab, omalizumab, omburtamab, OMS721, onartuzumab, ontuxizumab, onvatilimab, opicinumab, oportuzumab monatox, oregovomab, olticumab, otelixizumab, otilimab, otlertuzumab, oxelumab, ozanezumab, ozoralizumab, pasivaximab, palivizumab, pamrevlumab, panitumumab, pancomab, panobacumab, palsatuzumab, pascolizumab, pasotuxizumab, pateclizumab, patritumab, PDR001,Pembrolizumab, pemtumomab, perakizumab, pertuzumab, pexelizumab, pidilizumab, pinatuzumab vedotin, pintumomab, placumab, prezalumab, prozalizumab, pogalizumab, polatuzumab vedotin, ponezumab, polgabiximab, prasinezumab, prezalizumab, priliximab, pritoxaximab, pritumumab, PRO140, kilimumab, racotumomab, radletumab, rafivirumab, ralpancizumab, ramucirumab, ranevetomab, ranibizumab, raxibacumab, ravagalimab, ravuturizumab, levothyroxine ... Fanezumab, regavirumab, REGN-EB, relatolimab, lemtolumab, reslizumab, rilotumumab, linucumab, risankizumab, rituximab, rivavazumab pegol, lobatumumab, Rmab, loredumab, romilkimab, romosozumab, lontalizumab, rosmantuzumab, rovalpituzumab tesirin, rovelizumab, rozanolixizumab, ruplizumab, SA237, sacituzumab govitecan, samalizumab, samutamab vedotin, sarilumab, satralizumab, satumomab pendetide, secukinumab, selicrelumab, seribantu , cetoxaximab, setursumab, sevirumab, sibrotuzumab, SGN-CD19A, SHP647, sifalimumab, siltuximab, simtuzumab, siplizumab, siltratumab vedotin, sirukumab, sofituzumab vedotin, solanezumab, solitomab, sonepcizumab, sontuzumab, spartalizumab, stamulumab, sulesomab, sputabumab, stimulimab, subizumab, subratoxumab, tabalumab, tacatuzumab tetraxetan, tadocizumab, talaxumab, talizumab, talquetamab, tamtubetumab, tanezumab , taplitumomab paptox, talexuzumab, tabolimab, teclistamab, tefibazumab, terimomab alitox, telisotuzumab, telisotuzumab vedotin, tenatumomab, teneliximab, teplizumab, tepositamab, teprotumumab, tesidolumab, tetulomab, tezepelumab, TGN1412, tiburizumab, tildrakizumab, tigatuzumab, timigituzumab, timolumab, tiragolumab, tiragotumab, tislelizumab, tisotuzumab vedotin, TNX-650, tocilizumab, tomzotuximab, toralizumab, tosatoxumab,Tositumomab, tobetumab, tralokinumab, trastuzumab, trastuzumab duocarmazine, trastuzumab emtansine, TRBS07, tregalizumab, tremelimumab, trevoglumab, tucotuzumab celmoleukin, tuvilumab, ublituximab, urocupulumab, urelumab, urtoxazumab, ustekinumab, utomilumab, vadastuximab butarilin, banalimab, bundlestuzumab vedotin, vanticutumab, vanucizumab, bapaliximab, valisacumab, ba including lurilumab, batelizumab, vedolizumab, veltuzumab, bepalimomab, besencumab, visilizumab, bovalilizumab, volociximab, bonlerolizumab, bopratelimab, borsetuzumab mafodotin, votumumab, bunakizumab, xentuzumab, XMAB-5574, zalutumumab, zanolimumab, zatuximab, zenoctuzumab, diralimumab, zolbetuximab, (=IMAB362, claudiximab), zolimomab alitox, or combinations thereof; or (vi) the second therapeutic agent comprises an antibody or antigen-binding portion / fragment thereof effective to induce ADCC, ADCP and / or CDC; The anti-IGSF8 monoclonal antibody.

20. A pharmaceutical composition comprising a monoclonal antibody described in any one of claims 1 to 8.

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