Multi-functional fusion proteins and uses thereof

Abstract

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Description

5          Provided is a fusion protein. In some exemplary embodiments, said first component of the fusion protein blocks a chemokine receptor, e.g., CXCR4 and / or CXCR7 (via binding of a vMIPII or VI peptide or derivatives thereof in the fusion protein), and this blockade serves to immobilize the tumor cells and interfere with its migratory, invasive, metastatic, and other tumorigenic properties; said second component of the fusion protein blocks a checkpoint 10 inhibitor on said tumor cell, e.g., PD-L1 and / or PD-L2 (via binding of PD1 or derivatives thereof in the fusion protein), and this blockade serves to interfere with inhibition of a tumor-directed immune effector cell, e.g., an NK cell; and said third component of the fusion protein, triggers an activating receptor on the same immune effector cell, e.g., the FcyRIIIa receptor (via binding of Fcy or derivatives thereof in the fusion protein), that drives NK cell 15 activation and promotes ADCC and ADCP. In some exemplary embodiments, one component of the fusion protein blocks a checkpoint inhibitor on a tumor or other cell and two other components each trigger a distinct activating receptor on an immune effector cell. In some embodiments, where the checkpoint inhibitor is on a tumor cell, the fusion protein molecularly bridges an immune effector cell 20 and a target tumor cell. Further, the three interactions of the fusion protein, a combination of checkpoint inhibitory pathway blockade and activating receptor triggering, serve to functionally reinforce each other, all three cooperatively driving activation of said immune effector cell, e.g., an NK cell. In a preferred embodiment, the checkpoint inhibitor blocked by the fusion protein consists of PD-L1, PD-L2, CD113, CD112, CD155, or CD111, and the two 25 activating receptors co-triggered by the fusion protein are the FcyRIIIa receptor and 4-IBB on an NK cell. Fusion Proteins Provided is fusion protein comprising Component A and / or Component B; wherein 30 Component A comprises Component Y, Component Z2 and Component Z3; and wherein Component B comprises Component X’, Component Z2’ and Component Z3’. In some embodiments, Component B further comprises Component Zf. Thus, in some embodiments, Component B comprises Component X’, Component Zf, Component Z2’ and 2026204884   23 Jun 2026 Component Z3’. In some embodiments, Component A further comprises Component Zb Thus, in some embodiments, Component A comprises Component Y, Component Zb Component Z2 and Component Z3. 5          In some embodiments, the fusion protein further comprises Component C, wherein Component C comprises Component X and Component Cl’. In further embodiments, Component Cl’ comprises at least a portion of an immunoglobulin light chain. In some embodiments, the fusion protein further comprises Component D, wherein Component D comprises Component Q and Component Cl. In further embodiments, Component Cl 10 comprises at least a portion of an immunoglobulin light chain. In some embodiments, Component A further comprises a leader sequence. In further embodiments, the leader sequence is a human albumin leader sequence. In some embodiments, Component B further comprises a leader sequence. In further embodiments, the leader sequence is a human albumin leader sequence. 15          In some embodiments, Component Y comprises a ligand domain, a receptor domain, an scFv domain or a lipocalin domain. In further embodiments, Component Y comprises at least a portion of PD-1, TIGIT, CD96, CD112R, CD113, CD155, CD111, CD112, MHC-I polypeptide-related sequence A (MICA), NKG2A (CD94), MICB, ULBP1-5, TIM-3, CD226, NECL2, CRTAM, CD80, CTLA-4, KIR2DL1 / 2 / 3, or CD48. In yet further 20 embodiments, the fusion protein binds PD-L1 or PD-L2. In some embodiments, Component Zi comprises a domain of an immunoglobulin, a TNF superfamily member, aTNF-L superfamily member, a transferrin, a transferrin receptor, a human serum albumin or a lipocalin. In some embodiments, the domain of an immunoglobulin is a CHI domain. In some embodiments, the immunoglobulin is an IgG. In 25 yet further embodiments, the immunoglobulin is an IgE. In some embodiments, Component Z2 comprises a domain of an immunoglobulin, a TNF superfamily member, aTNF-L superfamily member, a transferrin, a transferrin receptor, a human serum albumin or a lipocalin. In some embodiments, the domain of an immunoglobulin is a CH2 domain. In some embodiments, the immunoglobulin is an IgG. In 30 yet further embodiments, the immunoglobulin is an IgE. In some embodiments, Component Z3 comprises a domain of an immunoglobulin, a TNF superfamily member, aTNF-L superfamily member, a transferrin, a transferrin receptor, a human serum albumin or a lipocalin. In some embodiments, the domain of an immunoglobulin is a CH3 domain. In some embodiments, the immunoglobulin is an IgG. In 2026204884   23 Jun 2026 yet further embodiments, the immunoglobulin is an IgE. In some embodiments, Component Zf comprises a domain of an immunoglobulin, a TNF superfamily member, aTNF-L superfamily member, a transferrin, a transferrin receptor, a human serum albumin or a lipocalin. In some embodiments, the domain of an 5 immunoglobulin is a CHI domain. In some embodiments, the immunoglobulin is an IgG. In yet further embodiments, the immunoglobulin is an IgE. In some embodiments, Component Z2’ comprises a domain of an immunoglobulin, a TNF superfamily member, aTNF-L superfamily member, a transferrin, a transferrin receptor, a human serum albumin or a lipocalin. In some embodiments, the domain of an 10 immunoglobulin is a CH2 domain. In some embodiments, the immunoglobulin is an IgG. In yet further embodiments, the immunoglobulin is an IgE. In some embodiments, Component Z3’ comprises a domain of an immunoglobulin, a TNF superfamily member, aTNF-L superfamily member, a transferrin, a transferrin receptor, a human serum albumin or a lipocalin. In some embodiments, the domain of an 15 immunoglobulin is a CH3 domain. In some embodiments, the immunoglobulin is an IgG. In yet further embodiments, the immunoglobulin is an IgE. In some embodiments, Component X’ comprises a virus-derived peptide, a ligand-derived, a receptor-derived peptide or a high-throughput screen (HTS)-selected peptide. In some embodiments, Component X’ comprises a peptide sequence that binds a chemokine 20 receptor, a cytokine receptor, a counter-receptor for a functional ligand, an integrin, a ligand, or a part of a membrane-signaling complex. In some embodiments, Component X’ comprises at least a portion of PD-1, TIGIT, CD96, CD112R, CD113, CD155, CD111, CD112, MHC-I polypeptide-related sequence A (MICA), NKG2A (CD94), MICB, ULBP1-5, TIM-3, CD226, NECL2, CRTAM, CD80, CTLA-4, KIR2DL1 / 2 / 3, or CD48. In further 25 embodiments, Component X’ comprises at least a portion of vMIP-II. In further embodiments, Component X’ comprises VI or VIdelta polypeptides. In yet further embodiments, the fusion protein binds CXCR4. In some embodiments, Component Q comprises at least a portion of PD-1, TIGIT, CD96, CD112R, CD113, CD155, CD111, CD112, MHC-I polypeptide-related sequence A 30 (MICA), NKG2A (CD94), MICB, ULBP1-5, TIM-3, CD226, NECL2, CRTAM, CD80, CTLA-4, KIR2DL1 / 2 / 3, or CD48. In some embodiments, Component X comprises a virus-derived peptide, a ligand-derived peptide, a receptor-derived peptide or an HTS-selected peptide. In further embodiments, Component X comprises VI or VI delta polypeptides. In further embodiments, 2026204884   23 Jun 2026 the fusion protein binds CXCR4. In some embodiments, Component Y and Component Z2 are connected via a hinge, for example an IgG hinge. In some embodiments, Component Zf and Component Z2’ are connected via a hinge, for example an IgG hinge. In some embodiments, Component X’ and 5 Component Zf are connected via a linker. In some embodiments, Component X and Component Cl are connected via a linker. In some embodiments, the fusion protein comprises Component A and Fc. In further embodiments, the fusion protein comprises Component A and human FcB (hFcB). In some embodiments, the fusion protein comprises Component B and Fc. In further 10 embodiments, the fusion protein comprises Component B and human FcA (hFcA). In some embodiments, Component A and Component B are covalently linked. In some embodiments, the covalent linkage is via a disulfide bond, or via a linker. In some embodiments, Component A and Component B are not covalently linked. In some embodiments, Component A and Component B are held together via knobs-into-holes 15 interactions. In some embodiments, Component A and Component B comprise knobs-into-holes mutations and covalent linkage via disulfide bond. In some embodiments, Component A comprises mutations Y349C and T366W, and Component B comprises mutations D356C, T366S, L368A and Y407V (“Knobs-into-holes” mutations). The positions of mutations and alterations in these component chains are defined by the Kabat numbering convention 20 (Johnson, G and Wu, TT, (2001) Nucleic Acids Res., 28(1), 214-18). In some embodiments, the fusion protein comprises Component A and a domain of an immunoglobulin. In some embodiments, the immunoglobulin domain is an Fc domain. In some embodiments, the fusion protein comprises Component B and a domain of an immunoglobulin. In some embodiments, the immunoglobulin domain is an Fc domain. 25          In some embodiments, Component B and Component C are covalently linked. In some embodiments, the covalent linkage is via a disulfide bond. In some embodiments, Component B and Component C are not covalently linked. In some embodiments, Component A and Component D are covalently linked. In some embodiments, the covalent linkage is via a disulfide bond. 30         In some embodiments, Component A and Component D are not covalently linked. In some embodiments, the fusion protein binds a receptor or ligand on an immune cell. In some embodiments, the receptor is an Fc receptor. Also provided is a pharmaceutical composition comprising a pharmaceutically 2026204884   23 Jun 2026 acceptable carrier and the fusion protein of any one of the preceding embodiments. Also provided is a method of treating a proliferative disorder in a patient comprising administering a therapeutically effective amount of the fusion protein of any one of the preceding embodiments to a patient in need of such treatment. In some embodiments, the 5 proliferative disorder is cancer. In further embodiments, the cancer is a solid tumor. In yet further embodiments, the cancer is pancreatic cancer, breast cancer, ovarian cancer, bladder cancer, melanoma, glioblastoma, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), multiple myeloma, colon cancer, lung cancer, liver cancer, or any solid or liquid tumor type. 10           The present invention provides novel fusion proteins useful for treating proliferative disorders, such as cancer. On a cell expressing a receptor or ligand for Component Y and a receptor or ligand for Component X’, the fusion protein of the invention may block one or both receptors or ligands. Thus, on a cell co-expressing a receptor or ligand for Component Y and a receptor or ligand for Component X’, the fusion protein of the invention may lead to 15 death, immobilization, and clearance of the tumor cell. Furthermore, on a cell expressing a receptor or ligand for Component Z3 or Component Z3’, for instance on a Natural Killer (NK) cell, the fusion protein of the invention may trigger the receptor or ligand, and may lead to activation of the cell. Thus, the fusion protein of the present invention may mediate its activity by spanning two neighboring cells. Further, the fusion protein of the present 20 invention may bind three or more distinct molecules on said cells. In some embodiments, the fusion protein may act to treat a disease such as cancer by causing inhibition or a reduction in certain cells, or activation or an increase in certain cells. Component A 25         Component A comprises Component Y, Component Z2 and Component Z3. Component Y In some embodiments, Component Y comprises a ligand domain, a receptor domain, a scFv domain or a lipocalin domain. In further embodiments, Component Y comprises at 30 least a portion of PD-1, TIGIT, CD96, CD112R, CD113, CD155, CD111, CD112, MHC-I polypeptide-related sequence A (MICA), NKG2A (CD94), MICB, ULBP1-5, TIM-3, CD226, NECL2, CRTAM, CD80, CTLA-4, KIR2DL1 / 2 / 3, or CD48. An exemplary sequence for component Y comprises or consists of: GWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSN 2026204884   23 Jun 2026 QTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAP KAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQ (SEQ ID NO: 1) Human PD-1 extracellular domain, GENBANK® Accession No. NM_005018.3. An exemplary sequence for component Y comprises or consists of: GWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFHVVWHRESPSG QTDTLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYVCGVISLAP KIQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQ 10          (SEQ ID NO: 2) High affinity human PD-1 extracellular domain. An exemplary sequence for component Y comprises or consists of: MMTGTIETTGNISAEKGGSIILQCHLSSTTAQVTQVNWEQQDQLLAICNADLG WHISPSFKDRVAPGPGLGLTLQSLTVNDTGEYFCIYHTYPDGTYTGRIFLEVLESSVA 15 EHGARFQIP (SEQ ID NO: 3) human TIGIT extracellular domain, GENBANK® Accession No. NM_173799.4. An exemplary sequence for component Y comprises or consists of: 20 VWEKTVNTEENVYATLGSDVNLTCQTQTVGFFVQMQWSKVTNKIDLIAVYHPQYG FYCAYGRPCESLVTFTETPENGSKWTLHLRNMSCSVSGRYECMLVLYPEGIQTKIYN LLIQTHVTADEWNSNHTIEIEINQTLEIPCFQNSSSKISSEFTYAWSVENSSTDSWVLLS KGIKEDNGTQETLISQNHLISNSTLLKDRVKLGTDYRLHLSPVQIFDDGRKFSCHIRVG PNKILRSSTTVKVFAKPEIPVIVENNSTDVLVERRFTCLLKNVFPKANITWFIDGSFLH 25 DEKEGIYITNEERKGKDGFLELKSVLTRVHSNKPAQSDNLTIWCMALSPVPGNKVW NISSEKITFLLGSEISSTDPPLSVTESTLDTQPSPASSVSPARYPATSSVTLVDVSALRPN TTPQPSNSSMTTRGFNYPWTSSGTDTKKSVSRIPSETYSSSPSGAGSTLHDNVFTSTAR AF SEVPTTANGSTKTNHVHITGIVVNKPKDGM (SEQ ID NO: 4) human CD96 extracellular domain, GENBANK® Accession No. 30   NM_198196.2. An exemplary sequence for component Y comprises or consists of: MGHRTLVLPWVLLTLCVTAGTPEVWVQVRMEATELSSFTIRCGFLGSGSISLV TVSWGGPNGAGGTTLAVLHPERGIRQWAPARQARWETQSSISLILEGSGASSPCANT 35 TFCCKFASFPEGSWEACGSLPPSSDPGLSAPPTPAPILRAD (SEQ ID NO: 5) human CD112R extracellular domain, GENBANK® Accession No. NM_024070.3. An exemplary sequence for component Y comprises or consists of: EEVLWHTSVPFAENMSLECVYPSMGILTQVEWFKIGTQQDSIAIFSPTHGMVI RKPYAERVYFLNSTMASNNMTLFFRNASEDDVGYYSCSLYTYPQGTWQKVIQVVQS 2026204884   23 Jun 2026 DSFEAAVPSNSHIVSEPGKNVTLTCQPQMTWPVQAVRWEKIQPRQIDLLTYCNLVHG RNFTSKFPRQIVSNCSHGRWSVIVIPDVTVSDSGLYRCYLQASAGENETFVMRLTVA EGKTDNQYTLFVA (SEQ ID NO: 6) human CD226 extracellular domain, GENBANK® Accession No. 5   NM_006566.3. An exemplary sequence for component Y comprises or consists of: QNLFTKDVTVIEGEVATISCQVNKSDDSVIQLLNPNRQTIYFRDFRPLKDSRFQ LLNFSSSELKVSLTNVSISDEGRYFCQLYTDPPQESYTTITVLVPPRNLMIDIQKDTAV 10 EGE EIEVNCTAMASKPATTIRWFKGNTELKGKSEVEEWSDMYTVTSQLMLKVHKEDDG VPV ICQVEHPAVTGNLQTQRYLEVQYKPQVHIQMTYPLQGLTREGDALELTCEAIGKPQP V 15 MVTWVRVDDEMPQHAVLSGPNLFINNLNKTDNGTYRCEASNIVGKAHSDYMLYVY DPPTTIPPPTTTTTTTTTTTTTILTIITDSRAGEEGSIRAVDH (SEQ ID NO: 7) human NECL2 extracellular domain, GENBANK® Accession No. NM_014333.3. 20          An exemplary sequence for component Y comprises or consists of: PIIVEPHVTAVWGKNVSLKCLIEVNETITQISWEKIHGKSSQTVAVHHPQYGFS VQGEYQGRVLFKNYSLNDATITLHNIGFSDSGKYICKAVTFPLGNAQSSTTVTVLVEP TVSLIKGPDSLIDGGNETVAAICIAATGKPVAHIDWEGDLGEMESTTTSFPNETATIIS QYKLFPTRFARGRRITCVVKHPALEKDIRYSFILDIQYAPEVSVTGYDGNWFVGRKG 25 VNLKCNADANPPPFKSVWSRLDGQWPDGLLASDNTLHFVHPLTFNYSGVYICKVTN SLGQRSDQKVIYISDPPTTTTLQPTIQWHPSTADIEDLATEPKKLPFPLSTLATIKDD (SEQ ID NO: 8) human CD113 extracellular domain, GENBANK® Accession No. NM_015480.3. 30          An exemplary sequence for component Y comprises or consists of: AEPHSLRYNLTVLSWDGSVQSGFLTEVHLDGQPFLRCDRQKCRAKPQGQWA EDVLGNKTWDRETRDLTGNGKDLRMTLAHIKDQKEGLHSLQEIRVCEIHEDNSTRSS QHFYYDGELFLSQNLETKEWTMPQSSRAQTLAMNVRNFLKEDAMKTKTHYHAMH ADCLQELRRYLKSGVVLRRTVPPMVNVTRSEASEGNITVTCRASGFYPWNITLSWRQ 35 DGVSLSHDTQQWGDVLPDGNGTYQTWVATRICQGEEQRFTCYMEHSGNHSTHPVP SGKVLVLQSHW (SEQ ID NO: 9) human MICA (MHC-I polypeptide-related sequence A) extracellular domain, GENBANK® Accession No. NM_000247.3. 40 Leader Sequence An exemplary sequence for the leader sequence comprises or consists of: MKWVTFISLLFLFSSAYS 2026204884   23 Jun 2026 (SEQ ID NO: 10) human albumin leader sequence. Hinge An exemplary sequence for the hinge comprises or consists of: 5       EPKSSDKTHTCPPCPAPELLGG (SEQ ID NO: 11) human IgG hinge. Component Z2 An exemplary sequence for component Z2 comprises or consists of: 10 PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAK (SEQ ID NO: 12) IgGl. Component Z; 15          An exemplary sequence for component Z3 comprises or consists of: GQPREPQVCTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO: 13) IgGl. 20          An exemplary sequence for component A comprises or consists of: Human PD-l-hFcA MKWVTFISLLFLFSSA ESASGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSE SFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRN 25 DSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQEPKSSDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEOYNSTYRVVSVLTVLHODWLNGKEYKCAVSNKALPAPIEKTI SKAKGOPREPOVCTLPPSRDELTKNOVSLWCLVKGFYPSDIAVEWESNGOPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWOOGNVFSCSVLHEALHSHYTOKSLSLSPGK 30 (SEQ ID NO: 14) Italics - human albumin leader sequence Wavy underline - human PD-1 extracellular domain; Y domain Bold - IgGl hinge region 35 Double underline - IgGl Z2 domain Bold underline - IgGl Z3 domain Another exemplary sequence for component A comprises or consists of: High affinity human PD-l-hFcA 40 M / HFJY / ’W / . / . / ’ / . / ’NS'zlESASGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSE SFHVVWHRESPSGQTDTLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRND 2026204884   23 Jun 2026 CPPCPAPEEEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEOYNSTYRVVSVLTVLHODWLNGKEYKCAVSNKALPAPIEKTIS KAKGOPREPOVCTLPPSRDELTKNOVSLWCLVKGFYPSDIAVEWESNGOPENNYKT TPPVLDSDGSFFLYSKLTVDKSRWOOGNVFSCSVLHEALHSHYTOKSLSLSPGK (SEQ ID NO: 15) Italics - human albumin leader sequence Wavy underline - high affinity human PD-1 extracellular domain; Y domain 10 Bold - IgGl hinge region Double underline - IgGl Z2 domain Bold underline - IgGl Z3 domain Another exemplary sequence for component A comprises or consists of: 15 Human CD112R-hFcA A / / \ nT77 / 5 / . / . / / . / XSJ IXASXIGHRTI AI JAVVId / lIX'VEXGTPEVWVQVRXlEATEE TIRCGFLGSGSISLVTVSWGGPNGAGGTTLAVLHPERGIRQWAPARQARWETQSSISL ILEGSGASSPCANTTFCCKFASFPEGSWEACGSLPPSSDPGLSAPPTPAPILRADEPKSS 20 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEOYNSTYRVVSVLTVLHODWLNGKEYKCAVSNKALPA PIEKTISKAKGOPREPOVCTLPPSRDELTKNOVSLWCLVKGFYPSDIAVEWESNGOPE NNYKTTPPVLDSDGSFFLYSKLTVDKSRWOOGNVFSCSVLHEALHSHYTOKSLSLSP GK 25 (SEQ ID NO: 16) Italics - human albumin leader sequence Wavy underline - human CD112R extracellular domain; Y domain Bold - IgGl hinge region 30 Double underline - IgGl Z2 domain Bold underline - IgGl Z3 domain Another exemplary sequence for component A comprises or consists of: Human TIGIT-hFcA 35 MKWVTFISLLFLFSSA ES'MMTGTIETTGNISAEKGGSIILQCHLSSTTAQVTQVNWEQQ DQLLAICNADLGWHISPSFKDRVAPGPGLGLTLQSLTVNDTGEYFCIYHTYPDGTYT GRIELEyLESSyAEHGAREQIPEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEOYNSTYRVVSVLT 40 VLHODWLNGKEYKCAVSNKALPAPIEKTISKAKGOPREPOVCTLPPSRDELTKNOVS LWCLVKGFYPSDIAVEWESNGOPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWOOG NVFSCSVLHEALHSHYTOKSLSLSPGK (SEQ ID NO: 17) 45 Italics - human albumin leader sequence Wavy underline - high affinity human TIGIT extracellular domain; Y domain Bold - IgGl hinge region Double underline - IgGl Z2 domain Bold underline - IgGl Z3 domain 2026204884   23 Jun 2026 10 15 Another exemplary sequence for component A comprises or consists of: Human CD96-hFcA MKWVTFISLLFLFSSA ES'VWEKTVNTEENVYATLGSDVNLTCQTQTVGFFVQMQWSK VTNKIDLIAVYHPQYGFYCAYGRPCESLVTFTETPENGSKWTLHLRNMSCSVSGRYE CMLyLYPEGIOTKIYNLLIOTHyTADEWNSNHTIEIEINQTLEIPCFQNSSSKISSEFTY VFPKANITWFIDGSFLHDEKEGIYITNEERKGKDGFLELKSVLTRVHSNKPAQSDNLTI WCMALSPVPGNKVWNISSEKITFLLGSEISSTDPPLSVTESTLDTQPSPASSVSPARYP ATSSVTLVDVSALRPNTTPQPSNSSMTTRGFNYPWTSSGTDTKKSVSRIPSETYSSSPS GAGSTLHDNVFTSTARAFSEVPTTANGSTKTNHVHITGIVVNKPKDGMEPKSSDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEOYNSTYRVVSVLTVLHODWLNGKEYKCAVSNKALPAPIEK TISKAKGOPREPOVCTLPPSRDELTKNOVSLWCLVKGFYPSDIAVEWESNGOPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWOOGNVFSCSVLHEALHSHYTOKSLSLSPGK (SEQ ID NO: 18) 20 Italics - human albumin leader sequence Wavy underline - human CD96 extracellular domain; Y domain Bold - IgGl hinge region Double underline - IgGl Z2 domain Bold underline - IgGl Z3 domain 25 Another exemplary sequence for component A comprises or consists of: Human CD226-hFcA MFWTF7S7ZFLFSN4ySEEVLWHTSVPFAENMSLECVYPSMGILTQVEWFKIGTQQDS 30 IAIFSPTHGMVIRKPYAERVYFLNSTMASNNMTLFFRNASEDDVGYYSCSLYTYPQG TWQKVIQVVQSDSFEAAVPSNSHIVSEPGKNVTLTCQPQMTWPVQAVRWEKIQPRQI DLLTYCNLVHGRNFTSKFPRQIVSNCSHGRWSVIVIPDVTVSDSGLYRCYLQASAGE NETFVMRETVAEGKTDNOYTEFVAEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKP KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEOYNSTYRV 35 VSVLTVLHODWLNGKEYKCAVSNKALPAPIEKTISKAKGOPREPOVCTLPPSRDELT KNOVSLWCLVKGFYPSDIAVEWESNGOPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WOOGNVFSCSVLHEALHSHYTOKSLSLSPGK (SEQ ID NO: 19) 40 Italics - human albumin leader sequence Wavy underline - human CD226 extracellular domain; Y domain Bold - IgGl hinge region Double underline - IgGl Z2 domain Bold underline - IgGl Z3 domain 45 Another exemplary sequence for component A comprises or consists of: Human NECL2-hFcA MFlP177757JJ7FYS^rYQNLFTKDVTVIEGEVATISCQVNKSDDSVIQLLNPNRQTIYF 2026204884   23 Jun 2026 5 EASNIVGKAHSDYMLYVYDPPTTIPPPTTTTTTTTTTTTTILTIITDSRAGEEGSIRAVD HEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEOYNSTYRVVSVLTVLHODWLNGKEYKCAVSN KALPAPIEKTISKAKGOPREPOVCTLPPSRDELTKNOVSLWCLVKGFYPSDIAVEWES NGOPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWOOGNVFSCSVLHEALHSHYTOK 10 SLSLSPGK (SEQ ID NO: 20) Italics - human albumin leader sequence Wavy underline - human NECL2 extracellular domain; Y domain 15 Bold - IgGl hinge region Double underline - IgGl Z2 domain Bold underline - IgGl Z3 domain Another exemplary sequence for component A comprises or consists of: 20  Human CD 113-hFcA A / / Grr / 7 / 5 / . / . / / . / AYnAASPIIVEPHVCW NAOSSTTVTVLVEPTVSLIKGPDSLIDGGNETVAAICIAATGKPVAHIDWEGDLGEME 25 STTTSFPNETATIISQYI<LFPTRFARGRRITCVVI<HPALEI<DIRYSFILDIQYAPEVSVT GYDGNWFVGRKGVNLKCNADANPPPFKSVWSRLDGQWPDGLLASDNTLHFVHPLT Eplstlatikddepkssdkthtcppcpapellggpsvflfppkpkdtlmisrtpevtc 30 VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEOYNSTYRVVSVLTVLHODWLN GKEYKCAVSNKALPAPIEKTISKAKGOPREPOVCTLPPSRDELTKNOVSLWCLVKGF YPSDIAVEWESNGOPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWOOGNVFSCSVLH EALHSHYTOKSLSLSPGK (SEQ ID NO: 21) 35 Italics - human albumin leader sequence Wavy underline - human CD113 extracellular domain; Y domain Bold - IgGl hinge region Double underline - IgGl Z2 domain Bold underline - IgGl Z3 domain Another exemplary sequence for component A comprises or consists of: 40 Human MICA-hFcA (MHC-I polypeptide-related sequence A) 45 A / / Grr / 7 / 5 / . / . / / . / XSJ}Y^W SGFYPWNITLSWRQDGVSLSHDTQQWGDVLPDGNGTYQTWVATRICQGEEQRFTC 2026204884   23 Jun 2026 YMEHSGNHSTHPyPSGKVL^ PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEOYNSTYRV VSVLTVLHODWLNGKEYKCAVSNKALPAPIEKTISKAKGOPREPOVCTLPPSRDELT KNOVSLWCLVKGFYPSDIAVEWESNGOPENNYKTTPPVLDSDGSFFLYSKLTVDKSR 5 WOOGNVFSCSVLHEALHSHYTOKSLSLSPGK (SEQ ID NO: 22) Italics - human albumin leader sequence Wavyjanderline - human MICA extracellular domain; Y domain 10 Bold - IgGl hinge region Double underline - IgGl Z2 domain Bold underline - IgGl Z3 domain 15 Human FcA MXJFFTF / SZZFZFS&4ESASEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMIS RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEOYNSTYRVVSVLTVL HODWLNGKEYKCAVSNKALPAPIEKTISKAKGOPREPOVCTLPPSRDELTKNOVSLW 20 CLVKGFYPSDIAVEWESNGOPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWOOGNV FSCSVLHEALHSHYTOKSLSLSPGK (SEQ ID NO: 23) Italics - human albumin leader sequence 25 Bold - IgGl hinge region Double underline - IgGl Z2 domain Bold underline - IgGl Z3 domain Component B 30         Component B comprises Component X’, Component Z2’ and Component Z3’. In some embodiments, Component X’ comprises a virus-derived peptide, a ligand-derived peptide, a receptor-derived peptide or an HTS-selected peptide. In some embodiments, Component X’ comprises at least a portion of PD-1, TIGIT, CD96, CD112R, CD113, CD155, CD111, CD112, MHC-I polypeptide-related sequence A (MICA), NKG2A (CD94), 35 MICB, ULBP1-5, TIM-3, CD226, NECL2, CRTAM, CD80, CTLA-4, KIR2DL1 / 2 / 3, or CD48. Component X’ An exemplary sequence for component X’ comprises or consists of: 40 WPPPGTGDVVVQAPTQVPGFLGDSVTLPCYLQVPNMEVTHVSQLTWARHGESGSM AVFHQTQGPSYSESKRLEFVAARLGAELRNASLRMFGLRVEDEGNYTCLFVTFPQGS RSVDIWLRVLAKPQNTAEVQKVQLTGEPVPMARCVSTGGRPPAQITWHSDLGGMPN TSQVPGFLSGTVTVTSLWILVPSSQVDGKNVTCKVEHESFEKPQLLTVNLTVYYPPEV SISGYDNNWYLGQNEATLTCDARSNPEPTGYNWSTTMGPLPPFAVAQGAQLLIRPV 2026204884   23 Jun 2026 DKPINTTLICNVTNALGARQAELTVQVKEGPPSEHSGMSRN (SEQ ID NO: 24) human CD155 (Polio virus receptor, PVR) extracellular domain, GENBANK® Accession No. NM_006505.5. 5          An exemplary sequence for component X’ comprises or consists of: MMTGTIETTGNISAEKGGSIILQCHLSSTTAQVTQVNWEQQDQLLAICNADLGWHISP SFKDRVAPGPGLGLTLQSLTVNDTGEYFCIYHTYPDGTYTGRIFLEVLESSVAEHGAR FQIP (SEQ ID NO: 25) human TIGIT (T cell immunoreceptor with Ig and ITIM domains) 10 extracellular domain, GENBANK® Accession No. NM_173799.4. An exemplary sequence for component X’ comprises or consists of: LEDGYKVEVGKNAYLPCSYTLPTSGTLVPMCWGKGFCPWSQCTNELLRTDE RNVTYQKSSRYQLKGDLNKGDVSLIIKNVTLDDHGTYCCRIQFPGLMNDKKLELKL 15 DIKAAKVTPAQTAHGDSTTASPRTLTTERNGSETQTLVTLHNNNGTKISTWADEIKD SGETIR (SEQ ID NO: 26) Mouse Tim-3 extracellular domain, GENBANK® Accession No. NM_134250.2. Mouse TIM-3 possesses good binding to human galactin-9. 20          An exemplary sequence for component X’ comprises or consists of: PIIVEPHVTAVWGKNVSLKCLIEVNETITQISWEKIHGKSSQTVAVHHPQYGFSVQGE YQGRVLFKNYSLNDATITLHNIGFSDSGKYICKAVTFPLGNAQSSTTVTVLVEPTVSLI KGPDSLIDGGNETVAAICIAATGKPVAHIDWEGDLGEMESTTTSFPNETATIISQYKLF PTRFARGRRITCVVKHPALEKDIRYSFILDIQYAPEVSVTGYDGNWFVGRKGVNLKC 25 NADANPPPFKSVWSRLDGQWPDGLLASDNTLHFVHPLTFNYSGVYICKVTNSLGQR SDQKVIYISDPPTTTTLQPTIQWHPSTADIEDLATEPKKLPFPLSTLATIKDD (SEQ ID NO: 27) human CD113 extracellular domain, GENBANK® Accession No. NM_015480.3. 30 Leader Sequence An exemplary sequence for the leader sequence comprises or consists of: MKWVTFISLLFLFSSAYS (SEQ ID NO: 10) human albumin leader sequence. 35 Hinge An exemplary sequence for the hinge comprises or consists of: EPKS SDKTHTCPPCP APELLGG (SEQ ID NO: 11) human IgG hinge. 2026204884   23 Jun 2026 Component Z2’ An exemplary sequence for component Z2 comprises or consists of: PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAK 5        (SEQIDNO: 12) IgGl. Component Z3’ An exemplary sequence for component Z3 comprises or consists of: GQPREPQVCTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPV 10 LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO: 13) IgGl. An exemplary sequence for component B comprises or consists of: Human CD155-hFcB 15 20 MXlP177VS7. / . / V. / <S;S7ESASWPPPGTGDVVVQAPTQVPGFLGDSVTLPCYLQVPNMEV RNEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEOYNSTYRVVSVLTVLHODWLNGKEYKCAVS NKALPAPIEKTISKAKGOPREPOVYTLPPSRCEETKNOVSLSCAVKGFYPSDIAVEWE 25 SNGOPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWOOGNVFSCSVLHEALHSHYTO KSLSLSPGK (SEQ ID NO: 32) Italics - human albumin leader sequence 30 Wavy underline - human CD155 (Polio virus receptor, PVR) extracellular domain; X’ domain Bold - IgGl hinge region Double underline - IgGl Z’2 domain Bold underline - IgGl Z’3 domain 35 Another exemplary sequence for component B comprises or consists of: Human TIGIT-hFcB MX1P177VS7J. / V. / ’NS'7 ESASMMTGTIETTGNISAEKGGSIILQCEILSSTTAQVTQVNWEQ 40 QDQLLAICNADLGWHISPSFKDRVAPGPGLGLTLQSLTVNDTGEYFCIYHTYPDGTY TGRIFLEVLESSVAEHGARFOIPEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDT LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEOYNSTYRVVSVL TVLHODWLNGKEYKCAVSNKALPAPIEKTISKAKGOPREPOVYTLPPSRCELTKNOV SLSCAVKGFYPSDIAVEWESNGOPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWOOG 45 NVFSCSVLHEALHSHYTOKSLSLSPGK 2026204884   23 Jun 2026 (SEQ ID NO: 33) Italics - human albumin leader sequence Wavy underline - human TIGIT (T cell immunoreceptor with Ig and ITIM domains) 5 extracellular domain; X’ domain Bold - IgGl hinge region Double underline - IgGl Z’2 domain Bold underline - IgGl Z’3 domain Another exemplary sequence for component B comprises or consists of: Mouse TIM-3-hFcB 10 MKWVTFISLLFLFSSA ESASLEDGYI<VEVGI<NAYLPCSYTLPTSGTLVPMCWGI<GFCP WSQCTNELLRTDERNVTYQI<SSRYQLI<GDLNI<GDVSLIII<NVTLDDHGTYCCRIQFP GLMNDI<I<LELI<LDII<AAI<VTPAQTAHGDSTTASPRTLTTERNGSETQTLVTLHNNN Gtkistwadeikdsgetirepkssdkthtcppcpapellggpsvflfppkpkdtlmis 15 RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEOYNSTYRVVSVLTVL HODWLNGKEYKCAVSNKALPAPIEKTISKAKGOPREPOVYTLPPSRCELTKNOVSLS CAVKGFYPSDIAVEWESNGOPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWOOGNV FSCSVLHEALHSHYTOKSLSLSPGK (SEQ ID NO: 34) 20 Italics - human albumin leader sequence Wavy underline - mouse TIM-3 extracellular domain; X’ domain Bold - IgGl hinge region Double underline - IgGl Z’2 domain 25 Bold underline - IgGl Z’3 domain Another exemplary sequence for component B comprises or consists of: Human CD 113-hFcB MKWVTFISLLFLFSSA ESASPIIVEPHVTAVWGI<NVSLI<CLIEVNETITQISWEI<IHGI<SS 30 35 NAQSSTTVTVLVEPTVSLIKGPDSLIDGGNETVAAICIAATGKPVAHIDWEGDLGEME GYDGNWFVGRKGVNLKCNADANPPPFKSVWSRLDGQWPDGLLASDNTLHFVHPLT FPLSTLATIKDDEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEOYNSTYRVVSVLTVLHODWLN GKEYKCAVSNKALPAPIEKTISKAKGOPREPOVYTLPPSRCELTKNOVSLSCAVKGF YPSDIAVEWESNGOPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWOOGNVFSCSVLH EALHSHYTOKSLSLSPGK (SEQ ID NO: 35) Italics - human albumin leader sequence Wavy underline - human CD113 extracellular domain; X’ domain Bold - IgGl hinge region Double underline - IgGl Z’2 domain 2026204884   23 Jun 2026 Bold underline - IgGl Z’3 domain Human FcB A / X1TET / WZ / V. / XX4FSASEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMIS 5 RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEOYNSTYRVVSVLTVL HODWLNGKEYKCAVSNKALPAPIEKTISKAKGOPREPOVYTLPPSRCELTKNOVSLS CAVKGFYPSDIAVEWESNGOPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWOOGNV FSCSVLHEALHSHYTOKSLSLSPGK (SEQ ID NO: 36) 10 Italics - human albumin leader sequence Bold - IgGl hinge region Double underline - IgGl Z’2 domain Bold underline - IgGl Z’3 domain 15 Component B comprising Component ZE In some embodiments, Component B further comprises Component ZE. Thus, in some embodiments, Components comprises ComponentX’, ComponentZf, Component Z2’ and Component Z3’. 20          In some embodiments, Component X’ comprises a virus-derived peptide, a ligand- derived peptide, a receptor-derived peptide or an HTS-selected peptide. In some embodiments, Component X’ comprises at least a portion of PD-1, TIGIT, CD96, CD112R, CD113, CD155, CD111, CD112, MHC-I polypeptide-related sequence A (MICA), NKG2A (CD94), MICB, ULBP1-5, TIM-3, CD226, NECL2, CRTAM, CD80, CTLA-4, 25   KIR2DL1 / 2 / 3, or CD48. In further embodiments, Component X’ comprises at least a portion ofCD155, TIGIT, TIM-3 or CD113. Component X’ An exemplary sequence for component X’ comprises or consists of: 30 LGASWHRPDKCCLGYQKRPLPQVLLSSWYPTSQLCSKPGVIFLTKRGRQVCADKSK DWVKKLMQQLPVTAR (SEQ ID NO: 37) vMIPII, GENBANK® Accession No. YP_001129362. An exemplary sequence for component X’ comprises or consists of: 35 LGASWHRPDKCCLGYQKRPLP (SEQ ID NO: 38) VI An exemplary sequence for component X’ comprises or consists of: LGASWHRPDKCALGYQKRPLP 2026204884   23 Jun 2026 (SEQ ID NO: 39) VIA An exemplary sequence for component X’ comprises or consists of: LGASWHRPDACALGYQKRPLP 5        (SEQ ID NO: 40) VlAmut An exemplary sequence for component X’ comprises or consists of: LGASWHRPDKCCLGYQKRPLPQVLLSSWYPTSQL (SEQ ID NO: 41) Vpl 10 An exemplary sequence for component X’ comprises or consists of: LGASWHRPDKCALGYQKRPLPQVLLSSWYPTSQL (SEQ ID NO: 42) VplA 15          An exemplary sequence for component X’ comprises or consists of: LGASWHRPDACALGYQKRPLPQVLLSSWYPTSQL (SEQ ID NO: 43) VplAmut Leader Sequence 20          An exemplary sequence for the leader sequence comprises or consists of: MKWVTFISLLFLFSSAYS (SEQ ID NO: 10) human albumin leader sequence. Component Zf 25          An exemplary sequence for component Zf comprises or consists of: SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVX (SEQ ID NO: 45) 30 Hinge An exemplary sequence for the hinge comprises or consists of: EPKSSDKTHTCPPCPAPELLGG (SEQ ID NO: 11) 35 Component Z2’ An exemplary sequence for component Z2’ comprises or consists of: PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAK (SEQ ID NO: 12) 2026204884   23 Jun 2026 Component Z3’ An exemplary sequence for component Z3’ comprises or consists of: GQPREPQVYTLPPSRCELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPV 5 LDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO: 48) An exemplary sequence for component B comprises or consists of: vMIPII-CH’-hFcB 10 MKWVTFISLLFLFSSA FYI XiA S \\H R14 ) KC C1 Xi Y Q K R1’ 1, PQ V1.1. S S \\Y PTS Q1.(’ S K1’ G VI FLTKRGRQVCADKSKDWyKKLMQQLPyTARSSASTKGPSVFPLAPSSKSTSGGTA ALGCLVKDYFPEVTVSWNSGALTSGVHTFPAVLOSSGLYSLSSVVTVPSSSLGTO TYICNVNHKPSNTKVDKKVXEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEOYNSTYRVVSVLT 15 VLHODWLNGKEYKCAVSNKALPAPIEKTISKAKGOPREPOVYTLPPSRCELTKNOVS LSCAVKGFYPSDIAVEWESNGOPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWOOG NVFSCSVLHEALHSHYTOKSLSLSPGK (SEQ ID NO: 49) 20 Italics - human albumin leader sequence Wavyunderhne - vMIPII BoldWavyunderline - Amino acid differences between VI, VIA and VlAmut Bold underline - CH’ Bold - IgGl hinge region 25 Double underline - IgGl Z’2 domain Bold underline - IgGl Z’3 domain An exemplary sequence for component B comprises or consists of: Vl-CH’-hFcB 3 0 MKWVTFISLLFLFSSA FXLGASWHRPDKCCLGYOKRPLPSSASTKGPSVFPLAPSSKS TSGGTAALGCLVKDYFPEVTVSWNSGALTSGVHTFPAVLOSSGLYSLSSVVTVPS SSLGTOTYTCNVNHKPSNTKVDKKVXEPKSSDKTHTCPPCPAPELLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEOYNSTY RVVSVLTVLHODWLNGKEYKCAVSNKALPAPIEKTISKAKGOPREPOVYTLPPSRCE 35 LTKNOVSLSCAVKGFYPSDIAVEWESNGOPENNYKTTPPVLDSDGSFFLVSKLTVDK SRWOOGNVFSCSVLHEALHSHYTOKSLSLSPGK (SEQ ID NO: 50) Italics - human albumin leader sequence 40 Wavy underline - VI (VI is the first 21 amino acids of VMIPII) Bold Wavy underline - Amino acid differences between VI, VIA and VlAmut Bold underline - CH’ Bold - IgGl hinge region Double underline - IgGl Z’2 domain 45 Bold underline - IgGl Z’3 domain 2026204884   23 Jun 2026 An exemplary sequence for component B comprises or consists of: VlA-CH’-hFcB MKWVTFISLLFLFSSA FSLGASWHRPDKCALGYQKRPLP SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEVTVSWNSGALTSGVHTFP 5 AVLOSSGLYSLSSVVTVPSSSLGTOTYICNVNHKPSNTKVDKKVXEPKSSDKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEOYNSTYRVVSVLTVLHODWLNGKEYKCAVSNKALPAPIEKTIS KAKGOPREPOVYTLPPSRCELTKNOVSLSCAVKGFYPSDIAVEWESNGOPENNYKTT PPVLDSDGSFFLVSKLTVDKSRWOOGNVFSCSVLHEALHSHYTOKSLSLSPGK 10 (SEQIDNO:51) Italics - human albumin leader sequence Wavyjanderhne - VIA (VIA is VI with a C to A mutation at amino acid 11 that increases dimerization of two VI peptides) 15   Bold W avy underline - Amino acid differences between V1, V1A and V1 Amut Bold underline - CH’ Bold - IgGl hinge region Double underline - IgGl Z’2 domain Bold underline - IgGl Z’3 domain 20 An exemplary sequence for component B comprises or consists of: VlAmut-CH’- hFcB MKWVTFISLLFLFSSA ESLG AS WHRPDAC A LGYQKRPLP SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEVTVSWNSGALTSGVHTFP 25 AVLOSSGLYSLSSVVTVPSSSLGTOTYICNVNHKPSNTKVDKKVXEPKSSDKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEOYNSTYRVVSVLTVLHODWLNGKEYKCAVSNKALPAPIEKTIS KAKGOPREPOVYTLPPSRCELTKNOVSLSCAVKGFYPSDIAVEWESNGOPENNYKTT PPVLDSDGSFFLVSKLTVDKSRWOOGNVFSCSVLHEALHSHYTOKSLSLSPGK 30 (SEQ ID NO: 52) Italics - human albumin leader sequence Wayyjjnderline - VI Amut (VI Amut has the same C to A mutation at amino acid 11 as VI but a K to A mutation at amino acid 9 was added that prevents receptor binding) 3 5                        - Amino acid differences between V1, V1A and V1 Amut Bold underline - CH’ Bold - IgGl hinge region Double underline - IgGl Z’2 domain Bold underline - IgGl Z’3 domain 40 An exemplary sequence for component B comprises or consists of: Vpl-CH’-hFcB MFWTF / 5ZZFZF55AFSLGASWHRPDKCCLGYQKRPLPQVLLSSWYPTS0LSS GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEVTVSWNSGALTSGVHTFPAVLOSS 45 GLYSLSSVVTVPSSSLGTOTYICNVNHKPSNTKVDKKVXEPKSSDKTHTCPPCPA PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA 2026204884   23 Jun 2026 KTKPREEOYNSTYRVVSVLTVLHODWLNGKEYKCAVSNKALPAPIEKTISKAKGOP REPOVYTLPPSRCELTKNOVSLSCAVKGFYPSDIAVEWESNGOPENNYKTTPPVLDS DGSFFLVSKLTVDKSRWOOGNVFSCSVLHEALHSHYTOKSLSLSPGK (SEQ ID NO: 53) 5 Italics - human albumin leader sequence Wayyjrnderline - Vpl (Vpl is the first 34 amino acids of vMIPII) Bold Wavy underline - Amino acid differences between VI, VIA and VlAmut Bold underline - CH’ 10 Bold - IgGl hinge region Double underline - IgGl Z’2 domain Bold underline - IgGl Z’3 domain An exemplary sequence for component B comprises or consists of: 15 VplA-CH’-hFcB A7A7FFTF7AAAFLF5&4F5LGASWHRPDKCALGYQKRPLPQVLLSSWYPTSQLSSASTK GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEVTVSWNSGALTSGVHTFPAVLOSS GLYSLSSVVTVPSSSLGTOTYICNVNHKPSNTKVDKKVXEPKSSDKTHTCPPCPA PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA 20 KTKPREEOYNSTYRVVSVLTVLHODWLNGKEYKCAVSNKALPAPIEKTISKAKGOP REPOVYTLPPSRCELTKNOVSLSCAVKGFYPSDIAVEWESNGOPENNYKTTPPVLDS DGSFFLVSKLTVDKSRWOOGNVFSCSVLHEALHSHYTOKSLSLSPGK (SEQ ID NO: 54) 25 Italics - human albumin leader sequence Wavy underI ine - V p 1A BoldWavyunderline - Amino acid differences between VI, VIA and VlAmut Bold underline - CH’ Bold - IgGl hinge region 30 Double underline - IgGl Z’2 domain Bold underline - IgGl Z’3 domain VplAmut-CH’- hFcB A / AJJ T77 7.S7. / .7 7.7 .S.S. H'.SI.GASW HRPDACAI.GYOKRPI.PQX'I.I.SSW YP I SOI.SSASTK 35 GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEVTVSWNSGALTSGVHTFPAVLOSS GLYSLSSVVTVPSSSLGTOTYICNVNHKPSNTKVDKKVXEPKSSDKTHTCPPCPA PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPREEOYNSTYRVVSVLTVLHODWLNGKEYKCAVSNKALPAPIEKTISKAKGOP REPOVYTLPPSRCELTKNOVSLSCAVKGFYPSDIAVEWESNGOPENNYKTTPPVLDS 40 DGSFFLVSKLTVDKSRWOOGNVFSCSVLHEALHSHYTOKSLSLSPGK (SEQ ID NO: 55) Italics - human albumin leader sequence Wavy underline - VplAmut 45 Bold W avy underline - Amino acid differences between V1, V1A and V1 Amut Bold underline - CH’ Bold - IgGl hinge region Double underline - IgGl Z’2 domain 2026204884   23 Jun 2026 Bold underline - IgGl Z’3 domain Component C 5          In some embodiments, the fusion protein further comprises Component C, wherein Component C comprises Component X and Component Cl’. Component X An exemplary sequence for component X comprises or consists of: LGASWHRPDKCCLGYQKRPLPQVLLSSWYPTSQLCSKPGVIFLTKRGRQVCADKSK DWVKKLMQQLPVTAR (SEQ ID NO: 37) vMIPII, GENBANK® Accession No. YP_001129362. An exemplary sequence for component X comprises or consists of: 10 LGASWHRPDKCCLGYQKRPLP (SEQ ID NO: 38) VI An exemplary sequence for component X comprises or consists of: LGASWHRPDKCALGYQKRPLP (SEQ ID NO: 39) VIA An exemplary sequence for component X comprises or consists of: LGASWHRPDACALGYQKRPLP (SEQ ID NO: 40) VlAmut An exemplary sequence for component X comprises or consists of: LGASWHRPDKCCLGYQKRPLPQVLLSSWYPTSQL 20        (SEQ ID NO: 41) Vpl An exemplary sequence for component X comprises or consists of: LGASWHRPDKCALGYQKRPLPQVLLSSWYPTSQL (SEQ ID NO: 42) VplA An exemplary sequence for component X comprises or consists of: LGASWHRPDACALGYQKRPLPQVLLSSWYPTSQL 25        (SEQ ID NO: 43) VplAmut In some embodiments, Component X and Component X’ are the same. In further 2026204884   23 Jun 2026 embodiments, Component X and Component X’ are different. Leader Sequence An exemplary sequence for the leader sequence comprises or consists of: MKWVTFISLLFLFSSAYS (SEQ ID NO: 10) human albumin leader sequence Component Cl’ An exemplary sequence for component Cl’ comprises or consists of: 5 KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 64) An exemplary sequence for component C comprises or consists of: vMIPII-CL’ 10 MKWVTFISLLFLFSSA K5LG A SWHRP D KCCLG YQ K R P L PQV LESS W Y PTS QLC S KP G VI FLTKRGRQVCADKSKDWVKKLMOOLPVTARKRTVAAPSVFIFPPSDEOLKSGTAS WCLLNNFYPREAKVOWKVDNALOSGNSOESVTEODSKDSTYSLSSTL TLSKAD YEKHKVYACEVTHOGLSSPVTKSFNRGEC (SEQ ID NO: 57) 15 Italics - human albumin leader sequence Wavy underl me - vMIPII Bold W avy underline - Amino acid differences between VI, VIA and VlAmut Bold underline - CL’ An exemplary sequence for component C comprises or consists of: 20 Vl-CL’ / V / / GTE77'757. / . / '7. / '5'5'4 K5LGASWHRPDKCCLGYOKRPLPKRTVAAPSVFIFPPSDEOL KSGTASWCLLNNFYPREAKVOWTCVDNALOSGNSOESVTEODSKDSTYSLSSTL TLSKAD YEKHKVYACEVTHOGLSSPVTKSFNRGEC (SEQ ID NO: 58) 25 Italics - human albumin leader sequence Wavy underline - VI BoldWavyunderline - Amino acid differences between VI, VIA and VlAmut Bold underline - CL’ 30 An exemplary sequence for component C comprises or consists of: V1A-CL’ MXIT177V57. / . / V75^^ KSGTASWCLLNNFYPREAKVOWTCVDNALOSGNSOESVTEODSKDSTYSLSSTL TLSKAD YEKHKVYACEVTHOGLSSPVTKSFNRGEC 2026204884   23 Jun 2026 (SEQ ID NO: 59) Italics - human albumin leader sequence Wavyjanderhne - VIA 5 Bold W avy underline - Amino acid differences between V1, V1A and V1 Amut Bold underline - CL’ An exemplary sequence for component C comprises or consists of: VlAmut-CL’ M / fIE17FF7. / .F / .F^ 10 KSGTASWCLLNNFYPREAKVOWKVDNALOSGNSOESVTEODSKDSTYSLSSTL TLSKADYEKHKVYACEVTHOGLSSPVTKSFNRGEC (SEQ ID NO: 60) Italics - human albumin leader sequence 15   Wavy underline - V1 Amut Bold Wavy underline - Amino acid differences between VI, VIA and VIAmut Bold underline - CL’ An exemplary sequence for component C comprises or consists of: Vpl-CL’ MFJ4FTF / 5LLFLF55Ay5LGASWHRPDKCCLGYQKRPLPQVLLSSWYPTSOLKRTVA 20 APSVFIFPPSDEOLKSGTASVVCLLNNFYPREAKVOWKVDNALOSGNSOESVTE ODSKDSTYSLSSTLTLSKADYEKHKVYACEVTHOGLSSPVTKSFNRGEC (SEQ ID NO: 61) Italics - human albumin leader sequence 25   Wayyjjnderhne - Vp 1 Bold Wavy underline - Amino acid differences between VI, VIA and VIAmut Bold underline - CL’ An exemplary sequence for component C comprises or consists of: VplA-CL’ 3 0 MKWVTFISLLFLFSSA ES'LGASWHRPDKCALGYOKRPLPOVLLSSWYPTSOLKRTVA APSVFTFPPSDEOLKSGTASVVCLLNNFYPREAKVOWKVDNALOSGNSOESVTE ODSKDSTYSLSSTLTLSKADYEKHKVYACEVTHOGLSSPVTKSFNRGEC (SEQ ID NO: 62) 35 Italics - human albumin leader sequence Wavyunderline - V p 1A Bold Wavy underline - Amino acid differences between VI, VIA and VIAmut Bold underline - CL’ 2026204884   23 Jun 2026 An exemplary sequence for component C comprises or consists of: VplAmut-CL’ A / / \ nT77 / 57. / . / / . / 5Xn.SlXiAS\\HRI4)ACAl.GYOKRI4.I4_W PSVFIFPPSDEOLKSGTASVVCLLNNFYPREAKVOWKVDNALOSGNSOESVTEO DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHOGLSSPVTKSFNRGEC 5 (SEQ ID NO: 63) Italics - human albumin leader sequence Wayyjjnderhne - VplAmut Bold Wavyunderline - Amino acid differences between VI, VIA and VlAmut 10 Bold underline - CL’ Component D In some embodiments, the fusion protein further comprises Component D, wherein Component D comprises Component Q and Component Cl. In some embodiments, 15 Component Q comprises at least aportion of PD-1, TIGIT, CD96, CD112R, CD113, CD155, CD 111, CD 112, MHC-I polypeptide-related sequence A (MICA), NKG2A (CD94), MICB, ULBP1-5, TIM-3, CD226, NECL2, CRTAM, CD80, CTLA-4, KIR2DL1 / 2 / 3, or CD48. An exemplary sequence for Component Q comprises or consists of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, Component Q and Component Y are the same. In 20 further embodiments, Component Q and Component Y are different. Component Cl An exemplary sequence for component Cl comprises or consists of: KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV 25 TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 64) Configuration of Fusion Protein In some embodiments of the fusion protein of the present invention, when prepared by 30   recombinant methods described elsewhere herein, the coding sequences of the components of Component A are fused together in frame, either directly or through a linker. As used herein, the term “directly” refers to a fusion of the two components without a peptide linker in between (i.e., in an expression construct, the codons encoding Component Y, Component Z2 and Component Z3 are contiguous). As used herein, “fused in frame” means that the 35   expression of the fused coding sequences results in the fusion protein comprising all of the polypeptide components, e.g., in some embodiments Component A comprises all of the polypeptide components of Component Y, Component Z2 and Component Z3 in frame. 2026204884   23 Jun 2026 In some embodiments of the fusion protein of the present invention, when prepared by recombinant methods described elsewhere herein, the coding sequences of the components of Component B are fused together in frame, either directly or through a linker. In some embodiments in an expression construct for Component B, the codons encoding Component 5   X’, Component Z2 and Component Z3’ are contiguous. In further embodiments, in an expression construct for component B, the codons encoding Component X’, Component Zf, Component Z2 and Component Z3’ are contiguous. In some embodiments, Component B comprises all of the polypeptide components of Component X’, Component Z2 and Component Z3’ in frame. In further embodiments, Component B comprises all of the 10 polypeptide components of Component X’, Component Zf, Component Z2’ and Component Z3’ in frame. In some embodiments of the fusion protein of the present invention, when prepared by recombinant methods described elsewhere herein, the coding sequences of the components of Component C are fused together in frame, either directly or through a linker. In some 15 embodiments in an expression construct for Component C, the codons encoding Component X and Component Cl’ are contiguous. In some embodiments, Component C comprises all of the polypeptide components of Component X and Component Cl’ in frame. In some embodiments, any Component A and any Component B can be mixed and matched with each other. In some exemplary embodiments of the fusion protein of the 20 invention, Component A and Component B are as shown in Table 1. In some embodiments, Component A and Component B from Table 1 can be mixed and matched with each other and with additional Component A and Component B options. Said additional options can also be mixed and matched with each other. Additional options of Component A or Component B may comprise at least a portion ofPD-1, TIGIT, CD96, CD112R, CD113, CD155, CD111, 25 CD112, MHC-I polypeptide-related sequence A (MICA), NKG2A (CD94), MICB, ULBP1-5, TIM-3, CD226, NECL2, CRTAM, CD80, CTLA-4, KIR2DL1 / 2 / 3, or CD48. In some embodiments, the fusion protein comprises a Component A and hFcB. In some embodiments, the fusion protein comprises a Component B and hFcA. In some exemplary embodiments, one component of the fusion protein blocks an 30 inhibitory receptor, and two other components of the fusion protein each trigger distinct activating receptors. In a preferred embodiment, these three receptors are co-located on the surface of the same immune effector cell, e.g., an NK cell, and the fusion protein’s three interactions, consisting of a combination of inhibitory receptor blockade and activating receptor triggering, serve to reinforce each other, all three cooperatively driving activation of 2026204884   23 Jun 2026 the NK cell. In other exemplary embodiments, two components of the fusion protein each block distinct inhibitory receptors, and one other component of the fusion protein triggers an activating receptor. In a preferred embodiment, these three receptors are co-located on the 5 surface of the same immune effector cell, e.g., an NK cell, and the fusion protein’s three interactions, consisting of a combination of inhibitory receptor blockade and activating receptor triggering, serve to functionally reinforce each other, all three cooperatively driving activation of the NK cell. In yet other exemplary embodiments, three components of the fusion protein each 10 triggers an activating receptor. In a preferred embodiment, these three receptors are colocated on the surface of the same immune effector cell, e.g., an NK cell, and the fusion protein’s three interactions, all consisting of activating receptor triggering, serve to functionally reinforce each other, all three cooperatively driving activation of the NK cell. For NK cells, an activating receptor in the aforementioned embodiments can be the 15 FcyRIIIa receptor that drives NK cell activation and promotes antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Table 1-Exemplary Components A and B Component A Component B Human PD-l-hFcA (SEQ ID NO: 14) Human CD155-hFcB (SEQ ID NO: 32) High affinity (HA) human PD-l-hFcA (SEQ ID NO: 15) Human TIGIT-hFcB (SEQ ID NO: 33) Human CD112R-hFcA (SEQ ID NO: 16) Mouse TIM-3-hFcB (SEQ ID NO: 34) Human CD113-hFcA (SEQ ID NO: 21) Human CD113-hFcB (SEQ ID NO: 35) Human MICA-hFcA (SEQ ID NO: 22) Human CD96-hFcA (SEQ ID NO: 18) Human TIGIT-hFcA (SEQ ID NO: 17) Human CD226-hFcA (SEQ ID NO: 19) Human NECL2-hFcA (SEQ ID NO: 20) 20          In some exemplary embodiments, the fusion protein comprises Component B and Component C. In some embodiments, any Component B and any Component C can be mixed and matched with each other. In some embodiments, Component B and Component C are as 2026204884   23 Jun 2026 shown in Table 2. In some embodiments, each row of Table 2 shows a pairing of a Component B and a Component C in a fusion protein. Table 2 Component B Component C vMIPII-CH’-hFcB (SEQ ID NO: 49) vMIPII-CL’ (SEQ ID NO: 57) Vl-CH’-hFcB (SEQ ID NO: 50) Vl-CL’ (SEQ ID NO: 58) VlA-CH’-hFcB (SEQ ID NO: 51) V1A-CL’ (SEQ ID NO: 59) VlAmut-CH’-hFcB (SEQ ID NO: 52) VlAmut-CL’ (SEQ ID NO: 60) Vpl-CH’-hFcB (SEQ ID NO: 53) Vpl-CL’ (SEQ ID NO: 61) VplA-CH’-hFcB (SEQ ID NO: 54) VplA-CL’ (SEQ ID NO: 62) VplAmut-CH’-hFcB (SEQ ID NO: 55) VplAmut-CL’ (SEQ ID NO: 63) In some embodiments, Component A and Component B are held together via disulfide bond stabilized knobs-into-holes interactions (KiHs-s). In some embodiments, Component A comprises mutations Y349C and T366W (e.g. SEQ ID NO: 29), and Component B comprises mutations D356C, T366S, L368A and Y407V (e.g. SEQ ID NO: 30) (“Knobs-into-holes” 10 mutations), enabling the enforced dimerization of Component A and Component B. The Zb Z2 and Z3 components are based upon the polypeptide amino acid backbone of the CHI, CH2 and CH3 domains of human IgGl, respectively. The positions of mutations and alterations in these component chains are defined by the Kabat numbering convention (Johnson, G and Wu, TT (2011) Nucleic Acids Res., 28(1), 214-18) and are based upon the wild-type human 15 IgGl sequence. Wild-type Human IgGl (CHI. CH2 and CH3 domains) (beginning with amino acid number 118) AiisSTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV 20 LQSSGLYSLSSVVTVPSSSLGTQTYICSooNVNHKPSNTKVDKKVEPKSCDKTHTCPP CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEOYNSTYwRVVSVLTVLHODWLNGKEYKCKVSNKALPAPIEKTISKA KGOPREPOVYTLPPSRDELTKNOVSLTCLVKGFYPSDIAVEWESNGOPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWOOGNVFSCSVMHEALHNHYTOKSLSLSPGK447 25 (SEQ ID NO: 28) Wavy underline - IgGl Zi domain Bold - IgGl hinge region Double underline - IgGl Z2 domain 2026204884   23 Jun 2026 Bold underline - IgGl Z3 domain In some embodiments, Component A comprises or consists of the following sequence (Y349C and T366W): 5 AiisSTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSVVTVPSSSLGTQTYIC2ooNVNHKPSNTKVDKKVEPKSS*DKTHTCPP CPAPETJ.GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEOYNSTY3ooRVVSVLTVLHODWLNGKEYKCA**VSNKALPAPIEKTIS KAKGOPREPOVCTLPPSRDELTKNOVSLTCLVKGFYPSDIAVEWESNGOPENNYKTT 10 PPVLDSDGSFFLYSKLTVDKSRWOOGNVFSCSVL***HEALHNS***YTOKSLSLSPG K447 (SEQ ID NO: 29) Wavy underline - IgGl Zi domain (SEQ ID NO: 67) (see e.g. Figure la) Bold - IgGl hinge region (SEQ ID NO: 68) 15 S* - Compared to wild-type, this mutation was added to the hinge region to eliminate an unpaired cysteine (C) which could bind aberrantly to another cysteine Double underline - IgGl Z2 domain (SEQ ID NO: 69) A** - Mutation added to reduce Clq binding (see e.g. Figure la) Bold underline - IgGl Z3 domain (SEQ ID NO: 44) 20   L*** and S*** - Mutations added to increase FcRn binding (see e.g. Figure la) In some embodiments, Component B comprises or consists of the following sequence (D356C, T366S, L368A and Y407V): AiixSTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV 25 LQSSGLYSLSSVVTVPSSSLGTQTYIC200NVNHKPSNTKVDKKVEPKSSDKTHTCPP CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEOYNSTY3ooRVVSVLTVLHODWLNGKEYKCAVSNKALPAPIEKTISKA KGOPREPOVYTLPPSRCELTKNOVSLSCAVKGFYPSDIAVEWESNGOPENNYKTTPP VLDSDGSFFLVSKLTVDKSRWOOGNVFSCSVLHEALHSHYTOKSLSLSPGK447 30 (SEQ ID NO: 30) Wavy underline - IgGl Zf domain The components shown in Tables 1 and 2 are meant to be exemplary and nonlimiting. 35          In some exemplary embodiments, one component of the fusion protein blocks a receptor on a tumor cell that contributes to said tumor cell’s tumorigenicity and / or metastatic potential; a second component of the fusion protein blocks a checkpoint inhibitor on said tumor cell; and a third component of the fusion protein triggers an activating receptor on an immune effector cell. Without wishing to be bound by theory, the fusion protein serves to 40 molecularly bridge an immune effector cell and a target tumor cell, and the second and third components of the fusion protein serve to reinforce each other through a combination of blocking a checkpoint inhibitor and triggering an activating receptor on an immune effector cell, e.g., an NK cell, together cooperatively driving activation of said immune effector cell. 2026204884   23 Jun 2026 In a preferred embodiment, said first component of the fusion protein blocks a chemokine receptor, e.g., CXCR4 and / or CXCR7 (via binding of a vMIPII or VI peptide or derivatives thereof in the fusion protein), and this blockade serves to immobilize the tumor cells and interfere with its migratory, invasive, metastatic, and other tumorigenic properties; 5 said second component of the fusion protein blocks a checkpoint inhibitor on said tumor cell, e.g., PD-L1 and / or PD-L2 (via binding of PD1 or derivatives thereof in the fusion protein), and this blockade serves to interfere with inhibition of a tumor-directed immune effector cell, e.g., an NK cell; and said third component of the fusion protein, triggers an activating receptor on the same immune effector cell, e.g., the FcyRIIIa receptor (via binding of Fcy or 10 derivatives thereof in the fusion protein), that drives NK cell activation and promotes ADCC and ADCP. A beneficial feature of said embodiment is the same fusion protein also coordinately modulates other immune cells, beyond NK cells, with a net anti-tumor effect (See Fig. 5). In some exemplary embodiments, one component of the fusion protein blocks a 15 checkpoint inhibitor on a tumor or other cell and the other two components each trigger a distinct activating receptor on an immune effector cell. Where the checkpoint inhibitor is on a tumor cell, the fusion protein in effect serves to molecularly bridge an immune effector cell and a target tumor cell. Further, the fusion protein’s three interactions, a combination of checkpoint inhibitory pathway blockade and activating receptor triggering, serve to 20 functionally reinforce each other, all three cooperatively driving activation of said immune effector cell, e.g., an NK cell. In a preferred embodiment, the checkpoint inhibitor blocked by the fusion protein consists of PD-L1, PD-L2, CD113, CD112, CD155, or CD111, and the two activating receptors co-triggered by the fusion protein are the FcyRIIIa receptor and 4-IBB on an NK cell (see Fig. 6). 25          In some exemplary embodiments, one component of the fusion protein blocks a checkpoint inhibitor on a tumor or other cell; a second component of the fusion protein blocks a coinhibitory receptor for the same or a different checkpoint inhibitor on an immune effector cell; and a third component of the fusion protein triggers an activating receptor on an immune effector cell. Where the checkpoint inhibitor is on a tumor cell, the fusion protein in 30 effect serves to molecularly bridge an immune effector cell and a target tumor cell, and the fusion protein’s three interactions, a combination of checkpoint inhibitory pathway blockade and activating receptor triggering, serve to functionally reinforce each other, all three cooperatively driving activation of said immune effector cell, e.g., an NK cell. In a preferred embodiment, the checkpoint inhibitor blocked by the first component of the fusion protein 2026204884   23 Jun 2026 consists of PD-L1, PD-L2, CD113, CD112, CD155, or CD111; the coinhibitory receptor on an NK cell blocked by the fusion protein consists of PD-1, TIGIT, CD96, or CD112R; and the activating receptor triggered by the fusion protein is the FcyRIIIa receptor the same NK cell (see Fig. 7). 5          In some exemplary embodiments, one component of the fusion protein blocks a ‘don’t each me’ inhibitory receptor on a tumor-associated macrophage of the Ml type, thereby unleashing its anti-tumor phagocytic and other activities; two other components of the fusion protein each trigger a distinct activating receptor on said tumor-associated macrophage. The fusion protein’s three interactions, a combination of blocking a macrophage inhibitory 10 pathway and triggering separate activating receptors on the macrophage, serve to functionally reinforce each other, all three cooperatively driving activation of the tumor-associated macrophage and promoting its anti-tumor functions. In a preferred embodiment, the ‘don’t eat me’ receptor blocked by the first component of the fusion protein is SIRPa; the activating receptors triggered by the fusion protein are CD40 and the FcyRIIIa receptor on the same 15 macrophage (see Fig. 8, left panel). In some exemplary embodiments, one component of the fusion protein blocks a ‘don’t each me’ inhibitory receptor on a tumor-associated macrophage of the Ml type, thereby unleashing its anti-tumor phagocytic and other activities; a second component of the fusion protein blocks a distinct inhibitory receptor on said macrophage; and a third component of the 20 fusion protein triggers an activating receptor on said tumor-associated macrophage. The fusion protein’s three interactions, a combination of blocking two macrophage inhibitory pathways and triggering an activating receptor on the macrophage, serve to functionally reinforce each other, all three cooperatively driving activation and / or anti-tumor effector functions of the tumor-associated macrophage. In a preferred embodiment, the ‘don’t eat me’ 25 receptor blocked by the first component of the fusion protein is SIRPa; the inhibitory receptor blocked by the second component of the fusion protein is PD-1; and the activating receptor triggered by the fusion protein is the FcyRIIIa receptor (see Fig. 8, right panel). Preferred embodiments of the fusion protein of the present invention comprise a cytokine, or a portion or derivative thereof, which can be incorporated in Component A, 30 Component B, Component C and / or Component D. This includes a wide range of cytokines well known to those familiar with the art, which fall into a number of different classes, e.g., interleukins, tumor necrosis factors, interferons, colony-stimulating factors, and others; have been ascribed various functions, with a range of activating or inhibitory properties, e.g., 2026204884   23 Jun 2026 adaptive immunity, pro-inflammatory signaling, anti-inflammatory signaling, stem cell modulation and differentiation, chemotaxis, phagocytosis, cytotoxicity, and anti-viral effects; and have been associated with a range of immune and non-immune cell targets, e.g., B cells, T cells, NK cells, macrophage / monocytes, dendritic cells, bone marrow stromal cells, stem 5 cells, fibroblasts, endothelial cells, and epithelial cells. Preferred embodiments comprise cytokines linked to adaptive immunity (e.g., IL-2, IL-4, IL-7, IL-9, IL-15, IL-21, GM-CSF); pro-inflammatory signaling [e.g., IL-1 family (IL-1, IL-18, IL-33, IL-36); IL-6 family (IL-6, IL-11, IL-31, CNTF, CT-1, LIF, OPN, OSM); TNFalpha family (TNFa, TNF|3, BAFF, APRIL); IL-17 family (IL-17A-F, IL-25); Type IIFN family (IFNa, IFN0, IFNk, Limitin); 10 Type II IFN family (IFNy); and Type III IFN family (IFNlambdal / IL-29), IFNlambda2 / IL-28A, IFNlambda3 / IL-28B)]; and anti-inflammatory signaling [IL-12 family (IL-12, IL-23, IL-27, IL-35); and IL-10 family (IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, IL-29)]. See Turner, Mark D., et al.: “Cytokines and Chemokines: At the Crossroads of Cell Signaling and Inflammatory Disease”, Biochimica et Biophysica Acta 1843 (2014) 2563-2582. 15 vMIP-II In some embodiments, a component of the fusion protein of the invention may comprise vMIP-II or a variant thereof. The viral Macrophage Inflammatory Protein-II (vMIP-II) is a chemokine that interacts with the CC and CXC chemokine receptors, including the CCR5 and CXCR4 chemokine receptors. CCR5 and CXCR4 are the principal coreceptors 20 required for cell entry of human immunodeficiency virus (HIV-1). CXCR4 may also be found on cancer cells, e.g. tumor cells. vMIP-II, a chemokine encoded by human herpesvirus 8 (HHV-8) (Moore, P.S., et al., Science, 274:1739-1744, 1996) displays diverse interactions with both CC and CXC chemokine receptors and inhibits HIV-1 entry mediated through CCR3, CCR5, and CXCR4. See U.S. Patent Publication No. 2003 / 0220482, which is hereby 25 incorporated by reference in its entirety. vMIP-II also binds CXCR7, which like CXCR4, has been implicated in tumorigenesis. VI (aa 1-21 of vMIP-II), and its related DVI (D amino acid isomer) display antagonistic activity against CXCR4 and CXCR7, but not against CCR5. vMIP inhibits binding of CXCL12, the natural ligand. In some embodiments, the A signifies a mutation at the 12th amino acid that causes dimerization between the two 30 peptides of the B and C component. In some embodiments, the Amut signifies a mutation at the 10th amino acid that prevents binding of the peptide, acting as a negative control. PD-1 In some embodiments, a component of the fusion protein of the invention may 2026204884   23 Jun 2026 comprise PD-1 or a variant thereof. PD-1 (Programmed cell death protein 1), also known as CD279, is a protein on the surface of cells that has a role in regulating the response of the immune system to the cells. PD-1 down-regulates the immune system and promotes selftolerance by suppressing T cell inflammatory activity. Without wishing to be bound by 5 theory, PD-1 acts as an immune checkpoint through at least two mechanisms. PD-1 promotes apoptosis of antigen-specific T cells in lymph nodes. PD-1 also reduces apoptosis in regulatory T cells. PD-1 binds the ligands PD-L1 and PD-L2, which are members of the B7 family. PD-L1 and PD-L2 are expressed on the surface of some tumor cells. PD-L1 expressed on tumor cells engages PD-1 on effector T cells and NK cells and inhibits their function. 10 Thus, PD-L1 expressed on tumor cells inhibits effector T cell anti-tumor activity. In some embodiments, the PD-1 variant of the fusion protein of the invention is high affinity PD-1. Native PD-1 has a relatively low affinity for its ligands, PD-L1 and PD-L2. Higher affinity variants of the PD-1 ectodomain would serve as greater competitive antagonists for its ligands. PD-1 contact residues between human PD-1 and PD-L1 were 15 mutated and then assessed for binding. High affinity PD-1 described herein has ten mutated amino acids that result in enhanced affinity for PD-L1 of greater than 10,000-fold. For further details, see Maute et al., PNAS, 112(47): 6506-6514, 2015. CD112R In some embodiments, a component of the fusion protein of the invention may 20 comprise CD112R or a variant thereof. CD112R is expressed on T cells and NK cells and inhibits activating responses. CD112, widely expressed on antigen-presenting cells and tumor cells, is the ligand for CD112R. CD112R competes with CD226, a coinhibitory receptor, for binding to CD112. Without wishing to be bound by theory, disrupting the CD112R-CD112 interaction may increase T cell response. Human CD112R contains a single extracellular IgV 25 domain. The CD112R fusion protein variant described herein consists of the entire ectodomain of human CD112R linked to the hinge, CH2 and CH3 domains of human IgGl. CD112R and variants may bind to its ligand, CD112, and serve as a competitive antagonist for native CD112R on NK cells and T cells, preventing inhibitory signaling. CD113 30          In some embodiments, a component of the fusion protein of the invention may comprise CD113 or a variant thereof. CD113, also known as poliovirus receptor-related 3 (PVRL3) or nectin-3, is a member of the immunoglobulin superfamily which forms part of adherens junctions. CD113 has been shown to interact, without limitation, with MLLT4, PARD3 and PTPRM. In addition, CD113 engages TIGIT, CD111, CD112, CD155 and itself. 2026204884   23 Jun 2026 The CD113 fusion protein variant described herein consists of the entire extracellular domain of native human CD113 linked to the hinge, CH2 and CH3 domains of human IgGl. Fusion proteins containing CD113 may serve as a competitive antagonist for native TIGIT on NK cells and T cells, preventing inhibitory signaling. Alternatively, CD113 fusion proteins may 5 bind to CD112, CD 155 and / or CD111 and block their engagement with the inhibitory receptors CD112R, TIGIT and CD96, respectively, restoring NK cell and T cell cytotoxicity and cytokine production. MICA In some embodiments, a component of the fusion protein of the invention may 10 comprise MHC class I polypeptide-related sequence A (MICA) or a variant thereof. MICA is a cell surface glycoprotein encoded by the MICA gene located within MHC locus. MICA is not associated with p2-microglobulin nor does it bind peptides as conventional MHC class I molecules do. Without wishing to be bound by theory, MICA may act as a stress-induced ligand for the NKG2D receptor. MICA is broadly recognized by NK cells, y8 T cells, and 15 CD8+ ap T cells that express NKG2D on their cell surface. Effector cytolytic responses of T cells and NK cells against tumor cells expressing MICA are initiated as a result of NKG2D-MICA binding. In some embodiments, the MICA variant consists of the entire MICA ectodomain linked to the hinge, CH2 and CH3 domains of human IgGl. MICA triggering of NKG2D signaling on NK cells and cytotoxic T cells is an important mediator of anti-tumor 20 activity. CD155 In some embodiments, a component of the fusion protein of the invention may comprise CD155 or a variant thereof. CD155 is a type I transmembrane glycoprotein in the immunoglobulin superfamily. In humans, CD155 is encoded by the poliovirus receptor 25 (PVR) gene. CD155 is involved in the establishment of intercellular adherens junctions between epithelial cells. The external domain of CD155 mediates cell attachment to the extracellular matrix molecule vitronectin, while its intracellular domain interacts with the dynein light chain Tctex-l / DYNLTl. In addition, CD155 engages NK cell inhibitory receptors, TIGIT and CD96, limiting NK cell cytotoxicity, and the activating receptor CD226 30   (DNAM-1). Fusion proteins containing the extracellular domain of CD155 may bind to TIGIT or CD96 on NK and T cells and serve as a competitive antagonist for endogenous CD155 expressed by tumor cells or antigen presenting cells (APC). CD155-containing fusion proteins may also bind to the costimulatory receptor, CD226, and induce NK cell-mediated 2026204884   23 Jun 2026 lysis of tumor targets. TIGIT In some embodiments, a component of the fusion protein of the invention may comprise TIGIT or a variant thereof. In some embodiments, the TIGIT is mouse TIGIT. In 5 further embodiments, the TIGIT is human TIGIT. In some embodiments, the TIGIT variant comprises the entire TIGIT extracellular IgV-like domain linked to the hinge, CH2 and CH3 domains of human IgGl. TIGIT, also known as T cell immunoreceptor with Ig and ITIM domains, is an immune receptor present on some T cells and NK cells. TIGIT is also known as WUCAM or 10 Vstm3. TIGIT binds to CD155(PVR) on cells such as dendritic cells (DCs) and macrophages with high affinity, and also to CD112(PVRL2) with lower affinity. TIGIT is a checkpoint inhibitor and is over expressed on tumor antigen-specific (TA-specific) CD8+ T cells and CD8+ tumor infiltrating lymphocytes (TILs) from individuals with cancer, e.g. melanoma. Without wishing to be bound by theory, blockade of TIGIT may lead to increased cell 15 proliferation, cytokine production, and degranulation of tumor antigen-specific CD8+ T cells and TIL CD8+ T cells. Fusion proteins containing TIGIT may bind to its receptors CD155(PVR) and CD112(PVRL2) and block their interaction with TIGIT on NK cells. Disrupting the interaction of TIGIT with its ligands on cancer cells will restore NK cell cytotoxic activity and cytokine production. 20 TIM-3 In some embodiments, a component of the fusion protein of the invention may comprise TIM-3 or a variant thereof. T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), also known as Hepatitis A virus cellular receptor 2 (HAVCR2), is a protein that in humans is encoded by the HAVCR2 gene. HAVCR2 is a cell surface molecule expressed on 25 IFNy producing CD4+ Thl and CD8+ Tel cells. TIM-3 expression has also been detected in Thl7 cells, regulatory T-cells, and innate immune cells (dendritic cells, NK cells, monocytes). TIM-3 is an immune checkpoint and mediates T cell exhaustion. Without wishing to be bound by theory, TIM-3 is upregulated in tumor infiltrating lymphocytes (TIL) in several cancers, including but not limited to lung, gastric, head and neck, schwannoma, 30 melanoma and follicular B-cell non-Hodgkin lymphoma. In some embodiments, the TIM-3 variant comprises the entire TIM-3 ectodomain, including the N-terminal IgV-like domain, linked to the hinge, CH2 and CH3 domains of human IgGl. Fusion proteins containing TIM-3 may bind to its natural ligands, Galectin-9, Ceacam-1 and Phosphatidyl serine, and block their interaction with endogenous TIM-3 expressed on NK cells, T cells and APC, reversing 2026204884   23 Jun 2026 T cell exhaustion and restoring NK cell cytotoxicity and cytokine production. Tumor cell receptor targets In some embodiments, the fusion protein, or one or more components thereof, binds to a tumor cell receptor target. In some embodiments, the fusion protein, or one or more 5 components thereof, prevents binding of a ligand to a tumor cell receptor target. In some embodiments, the tumor cell receptor targets comprise, without limitation, chemokine receptors, notch receptors, immune checkpoint inhibitors, and tumor vasculature ligands and receptors. In some embodiments, the chemokine receptor comprises CXCR4, CCR10 or CCR7. In some embodiments, the immune checkpoint inhibitor comprises PD-L1 or PD-L2. 10 In some embodiments, the tumor vasculature target comprises avp3, avp5, CD13 (aminopeptidase N), a target of an NGF motif peptide, or Tie2 (receptor for Angiopoietin-2). Immune cell receptor targets In some embodiments, the immune cell receptor target is CD40. In some embodiments, the fusion protein, or one or more components thereof comprises agonist CD40 15 scFv. In further embodiments, the immune cell receptor target is SIRPa. In some embodiments, the fusion protein, or one or more components thereof comprises antagonist SIRPa peptide. In some embodiments, the immune cell receptor target is 4-1BB. In some embodiments, the fusion protein, or one or more components thereof comprises agonist 4-1BB scFv or agonist 4-1BB peptide. 20          In some embodiments, the immune cell receptor target is CD96. In some embodiments, a component of the fusion protein of the invention may comprise CD96 or a variant thereof. In some embodiments, a component of the fusion protein of the invention may comprise an antagonist or an agonist of CD96. In some embodiments, a component of the fusion protein of the invention may 25 comprise CD226 or a variant thereof. In some embodiments, a component of the fusion protein of the invention may comprise an antagonist or an agonist of CD226. In some embodiments, a component of the fusion protein of the invention may comprise TIM-3 or a variant thereof. In some embodiments, a component of the fusion protein of the invention may comprise an antagonist or an agonist of TIM-3. 30          In some embodiments, the immune cell receptor target is CD111. In some embodiments, a component of the fusion protein of the invention may comprise CD111 or a variant thereof. In some embodiments, a component of the fusion protein of the invention may comprise an antagonist or an agonist of CD111. 2026204884   23 Jun 2026 In some embodiments, the immune cell receptor target is CD 112. In some embodiments, a component of the fusion protein of the invention may comprise CD112 or a variant thereof. In some embodiments, a component of the fusion protein of the invention may comprise an antagonist or an agonist of CD112. 5          In some embodiments, the immune cell receptor target is CD113. In some embodiments, a component of the fusion protein of the invention may comprise CD113 or a variant thereof. In some embodiments, a component of the fusion protein of the invention may comprise an antagonist or an agonist of CD113. In some embodiments, the immune cell receptor target is CD115. In some 10 embodiments, a component of the fusion protein of the invention may comprise CD115 or a variant thereof. In some embodiments, a component of the fusion protein of the invention may comprise an antagonist or an agonist of CD115. In some embodiments, the immune cell receptor target is TIGIT. In some embodiments, a component of the fusion protein of the invention may comprise TIGIT or a 15 variant thereof. In some embodiments, a component of the fusion protein of the invention may comprise an antagonist or an agonist of TIGIT. In some embodiments, the immune cell receptor target is KIR2DLl / 2 / or 3 or a variant thereof. In some embodiments, a component of the fusion protein of the invention may comprise KIR2DLl / 2 / or 3 or a variant thereof. In some embodiments, a component of the 20   fusion protein of the invention may comprise an antagonist or an agonist of KIR2DLl / 2 / or 3. In some embodiments, the immune cell receptor target is HLA-C. In some embodiments, a component of the fusion protein of the invention may comprise an antagonist or an agonist of HLA-C. In some embodiments, a component of the fusion protein of the invention may comprise an antagonist or an agonist of HLA-C. 25          In some embodiments, the immune cell receptor target is NKG2A (CD94) or a variant thereof. In some embodiments, a component of the fusion protein of the invention may comprise NKG2A (CD94) or a variant thereof. In some embodiments, a component of the fusion protein of the invention may comprise an antagonist or an agonist of NKG2A (CD94) or a variant thereof. 30          In some embodiments, the immune cell receptor target is HLA-E. In some embodiments, a component of the fusion protein of the invention may comprise an antagonist or an agonist of HLA-E. In some embodiments, a component of the fusion protein of the invention may comprise an antagonist or an agonist of HLA-E. In some embodiments, the immune cell receptor target is 2B4 or a variant thereof. In 2026204884   23 Jun 2026 some embodiments, a component of the fusion protein of the invention may comprise 2B4 or a variant thereof. In some embodiments, a component of the fusion protein of the invention may comprise an antagonist or an agonist of 2B4 or a variant thereof. In some embodiments, the immune cell receptor target is CD48 or a variant thereof. In 5 some embodiments, a component of the fusion protein of the invention may comprise an antagonist or an agonist of CD48. In some embodiments, a component of the fusion protein of the invention may comprise an antagonist or an agonist of CD48 or a variant thereof. In some embodiments, the immune cell receptor target is NKG2D or a variant thereof. In some embodiments, a component of the fusion protein of the invention may comprise 10 NKG2D or a variant thereof. In some embodiments, a component of the fusion protein of the invention may comprise an antagonist or an agonist of NKG2D or a variant thereof. In some embodiments, the immune cell receptor target is MICA / B or ULBPlor a variant thereof. In some embodiments, a component of the fusion protein of the invention may comprise an antagonist or an agonist of MICA / B or ULBP1. In some embodiments, a 15   component of the fusion protein of the invention may comprise an antagonist or an agonist of MICA / B or ULBP1 or a variant thereof. In any one of the preceding embodiments, the immune cell is an NK cell, a T cell, a dendritic cell (DC), an antigen-presenting cell (APC), a macrophage, or a tumor-associated macrophage (Ml). 20 Immune cell receptor or ligand In some embodiments, the fusion protein, or one or more components thereof, binds to an immune cell receptor or ligand. In some embodiments, binding to the immune cell receptor or ligand results in NK cell activation (cytokine production (IFNy and TNF), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular 25 phagocytosis (ADCP)). In some embodiments, the receptor is an Fc receptor. In some embodiments, binding to the Fc receptor results in NK cell activation (ADCC and ADCP). In some embodiments, the Fc receptor is an Fcy, Fce, Fcu. Fcg, or Fc<s receptor. In some embodiments, the immune cell receptor or ligand is a member of the TNF superfamily or a receptor thereof, a member of the TNF-L superfamily or a receptor thereof, transferrin or a 30 receptor thereof, human serum albumin or a receptor thereof, or a member of the lipocalin structural family or a receptor thereof. Linkers In some embodiments, the components of the fusion protein of the invention may be 2026204884   23 Jun 2026 optionally connected via a peptide linker. The residues for the linker may be selected from naturally occurring amino acids, non-naturally occurring amino acids, and modified amino acids. The linker will typically connect the carboxy terminus of the first component to the amino terminus of the second component. The linker may alter the distance between the two 5 structural components of the fusion protein, as well as alter the flexibility of this region. The linker may comprise any number of amino acids. The linker may thus comprise, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, or more amino acids. In some embodiments, the linker may be 10 composed of from 3 to 60 amino acid residues, from 3 to 40 amino acid residues, from 3 to 30 amino acid residues, from 3 to 24 amino acid residues, from 3 to 18 amino acid residues, or from 3 to 15 amino acid residues. The linker may comprise, for example, a repeating subsequence of 2, 3, 4, 5 or more amino acid residues, comprising 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more repeats of the sub-sequence. 15          Linkers may be naturally-occurring sequences or designed sequences. Peptide linkers useful in the fusion protein of the invention include, but are not limited to, glycine linkers, glycine-rich linkers, serine-glycine linkers, and the like. A glycine-rich linker comprises at least about 50% glycine and preferably at least about 60% glycine. In one embodiment, the linker comprises the amino acid sequence Gly-Ser, or repeats thereof. See, e.g. Huston, et al., 20 Methods in Enzymology, 203:46-88 (1991). In another embodiment, the linker comprises the amino acid sequence Gly-Lys, or repeats thereof. See, e.g., Whitlow et al., Protein Eng., 6:989 (1993). In another embodiment, the linker comprises the amino acid sequence Gly-Gly-Ser or repeats thereof. In another embodiment, the linker comprises the amino acid sequence Gly-Gly-Gly-Gly-Ser (SEQ ID NO: 29), or repeats thereof. In certain specific embodiments, 25 the linker comprises the amino acid sequence Gly-Gly-Gly-Ser-Gly-Gly-Gly-Ser (SEQ ID NO: 30). In certain embodiments, the linker contains from 2 to 12 repeats of Gly-Gly-Ser or Gly-Gly-Gly-Ser or Gly-Gly-Gly-Gly-Ser (SEQ ID NO: 29). See U.S. Pat. No. 6,541,219 for examples of peptide linkers. In one embodiment, the linker may comprise the sequence GDPLVTAASVLEFGGSGGGSEGGGSEGGGSEGGGSDI (SEQ ID NO: 31). 30          Linkers are useful for separating the two components of the fusion protein to enable proper folding of the components, to reduce potential steric problems, and / or to contribute to optimal receptor binding. The skilled artisan is familiar with the design and selection of peptide linkers. See, for instance, Robison et al., 1998, Proc. Natl. Acad. Sci. USA 95:59295934. Automated programs are also available for peptide linker design (e.g., Crasto etal., 2026204884   23 Jun 2026 2000, Protein Engineering 13:309-312). Optional other elements The fusion protein optionally may also include further elements apart from Component A, Component B, Component C and / or Component D. Such further elements 5 may include, without limitation: an initiator methionine, a signal peptide, an antigen polypeptide, a trimerization domain, a higher order multimerization domain, and a purification tag, such as His-6. An exemplary purification tag is ASHHHHHHM (SEQ ID NO: 46). In an embodiment, the fusion protein of the invention comprises an optional trimerization domain. 10           Fusion proteins of the invention optionally comprise a signal peptide. Signal peptides can be varied according to the needs of the user, the expression system, and other factors, as would be understood by one skilled in the art. Signal peptides are well known in the art, and any desired signal peptide can be used, including those recognized / predicted by publicly available signal peptide recognition software known to those skilled in the art. 15          In some embodiments, the fusion protein of the invention comprises a hinge region which allows for flexibility between components. See Lobner et al. (2016) Immunol. Reviews 270:113-131. In some embodiments, Component Y and ComponentZ2 are connected via a hinge, for example an IgG hinge. In some embodiments, Component Zf and Component Z2’ are connected via a hinge, for example an IgG hinge. 20         In some embodiments, a N-linked glycan is attached to an Asn on Component A and / or Component B. In some embodiments, a N-linked glycan is attached to Asn297 on Component A and / or Component B. Without wishing to be bound by theory, this may promote FcR binding and may promote structural integrity and thermal stability of the fusion protein. See Arnold et al. (2007) Annu Rev Immunol 25:21-50. 25         In some embodiments, Component A and / or Component B comprise a K to A mutation. In some embodiments, Component A and / or Component B comprise a K322A mutation. Without wishing to be bound by theory, this may reduce Clq binding and complement-mediated lysis. See Idusogie et al. (2000) J. Immunol 164:4178-4184. In some embodiments, Component A and Component B comprise knobs-into-holes 30 mutations. In some embodiments, Component A comprises mutations Y349C and T366W, and Component B comprises mutations D356C, T366S, L368A and Y407V (“Knobs-into-holes” mutations). Without wishing to be bound by theory, this may promote heterodimerization over homodimerization. See Merchant et al. (1998) Nature Biotech. 16:677-681. 2026204884   23 Jun 2026 In some embodiments, Component A and / or Component B comprise mutations that increase binding to neonatal Fc receptor (FcRn). In some embodiments, Component A and / or Component B comprises mutations M428L and N434S. Without wishing to be bound by theory, this may increase binding to neonatal Fc receptor (FcRn) on various cells, prolonging 5 serum half-life. See Kuo and Aveson (2011) mAbs 3:422-430. Trimerization domains Trimerization domains are well known in the art. Non-limiting examples of trimerization domains suitable as a heterologous trimerization domain in the fusion protein of the invention include: the GCN4 leucine zipper (Harbury et al., 1993, “A switch between 10 two-, three-, and four-stranded coiled coils in GCN4 leucine zipper mutants,” Science 262(5138): 1401-7); a 35 amino-acid sequence from lung surfactant protein (Hoppe et al., 1994, “A parallel three stranded alpha helical bundle at the nucleation site of collagen triplehelix formation” FEBS letters 344(2-3): 191-5); short, repeating heptad sequences from collagen (McAlinden et al., 2003, “Alpha-helical coiled-coil oligomerization domains are 15 almost ubiquitous in the collagen superfamily,” J Biol Chern. 278(43):42200-7. Epub 2003 Aug 14.); and the bacteriophage T4 fibritin “foldon” (see, e.g., Miroshnikov et al., 1998, “Engineering trimeric fibrous proteins based on bacteriophage T4 adhesins,” Protein Eng. 11(4):329-32). Exemplary trimerization domains are also disclosed in U.S. Patent Nos. 6,911,205 and 8,147,843, and U.S. Patent Publication Pub. 2010 / 0136032. An exemplary 20 trimerization sequence is the T4 “foldon” having the sequence: GYIPEAPRDGQAYVRKRGEWVLLSTFL (SEQ ID NO: 47). Another exemplary trimerization domain is from thrombospondin-1 and has the sequence: VTTLQDSIRKVTEENKELANELRR (SEQ ID NO: 56). Modification 25          The invention encompasses variants of the fusion proteins described herein. While in general it is desirable for variants to show enhanced ability for binding to a given molecule, in some embodiments, variants may be designed with slightly reduced activity as compared to other fusion proteins of the invention, for example in instances in which one would purposefully want to attenuate activity. Furthermore, variants or derivatives can be generated 30 that would have altered multimerization properties. Preferably, variants or derivatives of the fusion proteins of the present invention maintain the hydrophobicity / hydrophilicity of the amino acid sequence. In additional embodiments, the fusion protein of the invention is a variant and / or derivative of the amino acid sequence shown in SEQ ID NO: 14, 15, 16, 17, 18, 19, 20, 21, 2026204884   23 Jun 2026 22, 32, 33, 34, 35, 49, 50, 51, 52, 53, 54, 55, 65, 66, 67, 68, 69, 70, or 71. In one embodiment, variants of the fusion proteins of the present invention will have at least 80% or greater sequence identity or homology, as those terms are understood in the art, to SEQ ID NO: 14, 15, 16, 17, 18, 19, 20, 21, 22, 32, 33, 34, 35, 49, 50, 51, 52, 53, 54, 55, 65, 66, 67, 68, 69, 70, 5 or 71, more preferably at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or even 99% sequence identity SEQ ID NO: 14, 15, 16, 17, 18, 19, 20, 21, 22, 32, 33, 34, 35, 49, 50, 51, 52, 53, 54, 55, 65, 66, 67, 68, 69, 70, or 71. The invention also provides chemical modification of a fusion protein of the invention. Non-limiting examples of such modifications may include but are not limited to 10 aliphatic esters or amides of the carboxyl terminus or of residues containing carboxyl side chains, O-acyl derivatives of hydroxyl group-containing residues, andN-acyl derivatives of the amino-terminal amino acid or amino-group containing residues, e.g., lysine or arginine. Other derivatives of the fusion proteins of the present invention include incorporation of unnatural amino acid residues, or phosphorylated amino acid residues such as 15 phosphotyrosine, phosphoserine or phosphothreonine residues. Other potential modifications include sulfonation, biotinylation, or the addition of other moieties, particularly those which have molecular shapes similar to phosphate groups. Derivatives also include polypeptides modified by glycosylation. These can be made by modifying glycosylation patterns during synthesis and processing in various alternative 20 eukaryotic host expression systems, or during further processing steps. Methods for producing glycosylation modifications include exposing the fusion proteins to glycosylating enzymes derived from cells that normally carry out such processing, such as mammalian glycosylation enzymes. Alternatively, deglycosylation enzymes can be used to remove carbohydrates attached during production in eukaryotic expression systems. Additionally, one 25 can also modify the coding sequence so that glycosylation site(s) are added or glycosylation sites are deleted or disabled. Furthermore, if no glycosylation is desired, the proteins can be produced in a prokaryotic host expression system. Variants and / or derivatives of the fusion proteins of the invention can be prepared by chemical synthesis or by using site-directed mutagenesis (Gillman et al., Gene 8:81 (1979); 30 Roberts et al., Nature 328:731 (1987) or Innis (Ed.), 1990, PCR Protocols: A Guide to Methods and Applications, Academic Press, New York, N.Y.) or the polymerase chain reaction method (PCR; Saiki et al., Science 239:487 (1988)), as exemplified by Daugherty et al., Nucleic Acids Res. 19:2471 (1991)) to modify nucleic acids encoding the complete receptors. 2026204884   23 Jun 2026 In additional embodiments, the fusion proteins of the present invention may further comprise one or more additional polypeptide domains added to facilitate protein purification, to increase expression of the recombinant protein, or to increase the solubility of the recombinant protein. Such purification / expression / solubility facilitating domains include, but 5 are not limited to, metal chelating peptides such as histidine-tryptophan modules that allow purification on immobilized metals (Porath, 1992, Protein Expr Purif3-0.26328 1), protein A domains that allow purification on immobilized immunoglobulin, and the domain utilized in the FLAGS extension / affmity purification system (Immunex Corp, Seattle, Wash.). The inclusion of a cleavable linker sequence such as Factor Xa or enterokinase (Invitrogen, San 10 Diego, Calif) between the purification domain and the fusion of Components A and B is useful to facilitate purification. Fusion expression vectors include pGEX (Pharmacia, Piscataway, N.J.), pMAL (New England Biolabs, Beverly, Mass.) and pRITS (Pharmacia, Piscataway, N.J.) which fuse glutathione S transferase (GST), maltose B binding protein, or protein A, respectively, to the 15 target recombinant protein. EBV, BKV, and other episomal expression vectors (Invitrogen) can also be used. In addition, retroviral and lentiviral expression vectors can also be used. Furthermore, any one of a number of in vivo expression systems designed for high level expression of recombinant proteins within organisms can be invoked for producing the fusion proteins specified herein. 20          As discussed above, a fusion protein of the present invention may contain a heterologous signal sequence at its N-terminus. In certain host cells (e.g., mammalian host cells), expression and / or secretion of the fusion protein can be increased through use of a heterologous signal sequence. Signal sequences are typically characterized by a core of hydrophobic amino acids, which are generally cleaved from the mature protein during 25 secretion in one or more cleavage events. Such signal peptides contain processing sites that allow cleavage of the signal sequence from the mature proteins as they pass through the secretory pathway. Thus, the invention pertains to the described polypeptides having a signal sequence, as well as to polypeptides from which the signal sequence has been proteolytically cleaved (i.e., the cleavage products). 30           In order to enhance stability and / or reactivity, the fusion protein of the present invention can also be modified to incorporate one or more polymorphisms in the amino acid sequence resulting from natural allelic variation. Additionally, D-amino acids, non-natural amino acids or non-amino acid analogues can be substituted or added to produce a modified fusion protein within the scope of this invention. 2026204884   23 Jun 2026 The amino acid sequences of the present invention may be produced by expression of a nucleotide sequence coding for same in a suitable expression system. In addition, or in the alternative, the fusion protein itself can be produced using chemical methods to synthesize the desired amino acid sequence, in whole or in part. For 5 example, polypeptides can be synthesized by solid phase techniques, cleaved from the resin, and purified by preparative high-performance liquid chromatography (e.g., Creighton (1983) Proteins: Structures And Molecular Principles, WH Freeman and Co, New York N.Y.). The composition of the synthetic polypeptides may be confirmed by amino acid analysis or sequencing (e.g., the Edman degradation procedure). Additionally, the amino acid sequence 10 of a fusion protein of the invention, or any part thereof, may be altered during direct synthesis and / or combined using chemical methods with a sequence from other subunits, or any part thereof, to produce a variant polypeptide. Assays for measuring the biological activity of any homolog, derivative or variant of any fusion protein of the present invention are well known in the art. 15 Activity and Utility In one embodiment, the fusion proteins of the present invention reduce or prevent a tumor cell from migrating, infiltrating neighboring tissues, and / or metastasizing to distant sites, in effect immobilizing said cell. In another embodiment, the fusion proteins of the present invention reduce or prevent a tumor cell from evading phagocytosis by a 20 phagocytotic cell, such as a macrophage, while also promoting apoptosis and / or immune destruction of the tumor cell. In other embodiments, the fusion proteins of the invention reduce or prevent a tumor cell from evading phagocytosis by a phagocytotic cell, while promoting apoptosis of a neighboring tumor cell. Thus, the fusion proteins of the present invention promote tumor cell destruction by any one of a number of mechanisms. 25          PD-1 ligands or receptors are expressed on a wide range of tumor cells, such a solid tumor cells. Thus, in one embodiment, the invention provides a method of treating a proliferative disorder by administering a therapeutically effective amount of a fusion protein of the invention to a subject diagnosed with a proliferative disorder. The fusion proteins according to the invention may be administered to individuals 30 (such as mammals, including animals and humans) afflicted with a cellular proliferative disorder such as cancer, and malignant and benign tumors. In a particular embodiment of the invention, the individual treated is a human. The fusion proteins are believed effective against a broad range of tumor types, including but not limited to the following: ovarian cancer; cervical cancer; breast cancer; 2026204884   23 Jun 2026 prostate cancer; testicular cancer, lung cancer, renal cancer; colorectal cancer; skin cancer; brain cancer; leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoid leukemia, and chronic lymphoid leukemia. More particularly, cancers that may be treated by the compounds, compositions and 5 methods of the invention include, but are not limited to, the following: cardiac cancers, including, for example sarcoma, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma; fibroma; lipoma and teratoma; lung cancers, including, for example, bronchogenic carcinoma, e.g., squamous cell, 10 undifferentiated small cell, undifferentiated large cell, and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchial adenoma; sarcoma; lymphoma; chondromatous hamartoma; and mesothelioma; gastrointestinal cancer, including, for example, cancers of the esophagus, e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; cancers of the 15 stomach, e.g., carcinoma, lymphoma, and leiomyosarcoma; cancers of the pancreas, e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, and vipoma; cancers of the small bowel, e.g., adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma; cancers of the large bowel, e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and 20 leiomyoma; genitourinary tract cancers, including, for example, cancers of the kidney, e.g., adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, and leukemia; cancers of the bladder and urethra, e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; cancers of the prostate, e.g., adenocarcinoma, and sarcoma; cancer of the 25 testis, e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, and lipoma; liver cancers, including, for example, hepatoma, e.g., hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and 30 hemangioma; bone cancers, including, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochrondroma (osteocartilaginous exostoses), benign chondroma, 2026204884   23 Jun 2026 chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; nervous system cancers, including, for example, cancers of the skull, e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans; cancers of the meninges, e.g., meningioma, meningiosarcoma, and gliomatosis; cancers of the brain, e.g., astrocytoma, 5 medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors; and cancers of the spinal cord, e.g., neurofibroma, meningioma, glioma, and sarcoma; gynecological cancers, including, for example, cancers of the uterus, e.g., endometrial carcinoma; cancers of the cervix, e.g., cervical carcinoma, and pre-tumor cervical dysplasia; 10 cancers of the ovaries, e.g., ovarian carcinoma, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, and malignant teratoma; cancers of the vulva, e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma; cancers of the vagina, e.g., clear cell carcinoma, squamous cell carcinoma, 15 botryoid sarcoma, and embryonal rhabdomyosarcoma; and cancers of the fallopian tubes, e.g., carcinoma; hematologic cancers, including, for example, cancers of the blood, e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, and myelodysplastic syndrome, 20 Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma) and Waldenstrom's macroglobulinemia, angioimmunoblastic T-cell lymphoma (AITL), chronic lymphocytic leukemia (CLL), acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, 25 Naegeli leukemia, plasma cell leukemia, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, aleukocythemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, undifferentiated cell leukemia, eosinophilic 30 leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell 2026204884   23 Jun 2026 leukemia, megakaryocytic leukemia and micromyeloblastic leukemia; skin cancers, including, for example, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and 5          adrenal gland cancers, including, for example, neuroblastoma. More particular examples of such cancers include kidney or renal cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, squamous cell cancer (e.g. epithelial squamous cell cancer), cervical cancer, ovarian 10 cancer, prostate cancer, liver cancer, bladder cancer, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, gastrointestinal stromal tumors (GIST), pancreatic cancer, head and neck cancer, glioblastoma, retinoblastoma, astrocytoma, thecomas, arrhenoblastomas, hepatoma, hematologic malignancies including non-Hodgkins lymphoma (NHL), multiple myeloma and acute hematologic malignancies, 15 endometrial or uterine carcinoma, endometriosis, fibrosarcomas, choriocarcinoma, salivary gland carcinoma, vulval cancer, thyroid cancer, esophageal carcinomas, hepatic carcinoma, anal carcinoma, penile carcinoma, nasopharyngeal carcinoma, laryngeal carcinomas, Kaposi's sarcoma, melanoma, skin carcinomas, Schwannoma, oligodendroglioma, neuroblastomas, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcomas, urinary tract carcinomas, thyroid 20 carcinomas, Wilm's tumor, as well as B-cell lymphoma (including low grade / follicular non Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade / follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia); chronic 25 lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); acute myelogenous leukemia (AML); Hairy cell leukemia; chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs' syndrome. “Tumor”, as used herein, refers to all neoplastic cell growth and proliferation, whether 30 malignant or benign, and all pre-cancerous and cancerous cells and tissues. Cancers may be solid tumors that may or may not be metastatic. Cancers may also occur, as in leukemia, as a diffuse tissue. Thus, the term "tumor cell", as provided herein, includes a cell afflicted by any one of the above identified disorders. In a preferred embodiment, the cancer is a solid tumor. In preferred embodiments, the 2026204884   23 Jun 2026 cancer is one of pancreatic cancer, breast cancer, ovarian cancer, bladder cancer, melanoma and glioblastoma. In another embodiment, the cancer is a hematologic cancer. In preferred embodiments, the hematological cancer is one of acute lymphoblastic leukemia (ALL) and 5 acute myelogenous leukemia (AML). Pharmaceutical Compositions and Dosing Regimens Administration of the compositions of the invention is typically parenteral, by subcutaneous, intravenous, intramuscular, or intraperitoneal injection, or by infusion or by any other acceptable systemic method. In a preferred embodiment, administration is by 10 subcutaneous injection. In another preferred embodiment, administration is by intravenous infusion, which may typically take place over a time course of about 1 to 5 hours. In addition, there are a variety of oral delivery methods for administration of therapeutic proteins, and these can be applied to the therapeutic fusion proteins of this invention. Often, treatment dosages are titrated upward from a low level to optimize safety and 15 efficacy. Generally, daily dosages will fall within a range of about 0.01 to 20 mg protein per kilogram of body weight. Typically, the dosage range will be from about 0.1 to 5 mg protein per kilogram of body weight. Various modifications or derivatives of the fusion proteins, such as addition of polyethylene glycol chains (PEGylation), may be made to influence their pharmacokinetic and / or pharmacodynamic properties. 20           To administer the fusion protein by other than parenteral administration, it may be necessary to coat the protein with, or co-administer the protein with, a material to prevent its inactivation. For example, protein may be administered in an incomplete adjuvant, coadministered with enzyme inhibitors or in liposomes. Enzyme inhibitors include pancreatic trypsin inhibitor, diisopropylfluorophosphate (DEP) and trasylol. Liposomes include water-25 in-oil-in-water CGF emulsions as well as conventional liposomes (Strejan etal., 1984, J. Neuroimmunol. 7:27). Although the compositions of the invention can be administered in simple solution, they are more typically used in combination with other materials such as carriers, preferably pharmaceutically acceptable carriers. Useful pharmaceutically acceptable carriers can be any 30 compatible, non-toxic substance suitable for delivering the compositions of the invention to a patient. Sterile water, alcohol, fats, waxes, and inert solids may be included in a carrier. Pharmaceutically acceptable adjuvants (buffering agents, dispersing agents) may also be incorporated into the pharmaceutical composition. Generally, compositions useful for parenteral administration of such drugs are well known; e.g., Remington's Pharmaceutical 2026204884   23 Jun 2026 Science, 17th Ed. (Mack Publishing Company, Easton, Pa., 1990). Alternatively, compositions of the invention may be introduced into a patient's body by implantable drug delivery systems (Urquhart et al., 1984, Ann. Rev. Pharmacol. Toxicol. 24:199). Therapeutic formulations may be administered in many conventional dosage 5 formulations. Formulations typically comprise at least one active ingredient, together with one or more pharmaceutically acceptable carriers. Formulations may include those suitable for oral, rectal, nasal, or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The formulations may conveniently be presented in unit dosage form and may be 10 prepared by any methods well known in the art of pharmacy. See, e.g., Gilman et al. (eds.) (1990), The Pharmacological Bases of Therapeutics, 8th Ed., Pergamon Press; and Remington's Pharmaceutical Sciences, supra, Easton, Pa.; Avis et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Dekker, N.Y.; Lieberman et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Dekker, N.Y.; and Lieberman et al. 15 (eds.) (1990), Pharmaceutical Dosage Forms: Disperse Systems, Dekker, N.Y. In additional embodiments, the present invention contemplates administration of the fusion proteins by gene therapy methods, e.g., administration of an isolated nucleic acid encoding a fusion protein of interest. The protein building blocks (e.g., Component A and Component B) of the fusion protein of the present invention have been well-characterized, 20 both as to the nucleic acid sequences encoding the proteins and the resultant amino acid sequences of the proteins. Engineering of such isolated nucleic acids by recombinant DNA methods is well within the ability of one skilled in the art. Codon optimization, for purposes of maximizing recombinant protein yields in particular cell backgrounds, is also well within the ability of one skilled in the art. Administration of an isolated nucleic acid encoding the 25 fusion protein is encompassed by the expression “administering a therapeutically effective amount of a fusion protein of the invention.” Gene therapy methods are well known in the art. See, e.g., WO96 / 07321 which discloses the use of gene therapy methods to generate intracellular antibodies. Gene therapy methods have also been successfully demonstrated in human patients. See, e.g., Baumgartner et al., 1998, Circulation 97: 12, 1114-1123, and more 30 recently, Fatham, 2007, “A gene therapy approach to treatment of autoimmune diseases,” Immun. Res. 18:15-26; and U.S. Pat. No. 7,378,089, both incorporated herein by reference. See also Bainbridge et al., 2008, “Effect of gene therapy on visual function in Leber's congenital Amaurosis,” N Engl Med 358:2231-2239; and Maguire et al.,2008, “Safety and efficacy of gene transfer for Leber's congenital Amaurosis,” N Engl J Med 358:2240-8. 2026204884   23 Jun 2026 There are two major approaches for introducing a nucleic acid encoding the fusion protein (optionally contained in a vector) into a patients cells: in vivo and ex vivo. For in vivo delivery, the nucleic acid is injected directly into the patient, usually at the site where the fusion protein is required. For ex vivo treatment, the patient's cells are removed, the nucleic 5 acid is introduced into these isolated cells and the modified cells are administered to the patient either directly or, for example, encapsulated within porous membranes which are implanted into the patient (see, e.g., U.S. Pat. Nos. 4,892,538 and 5,283,187). There are a variety of techniques available for introducing nucleic acids into viable cells. The techniques vary depending upon whether the nucleic acid is transferred into cultured cells in vitro, or in 10 vivo in the cells of the intended host. Techniques suitable for the transfer of nucleic acid into mammalian cells in vitro include the use of liposomes, electroporation, microinjection, cell fusion, DEAE-dextran, the calcium phosphate precipitation method, etc. Commonly used vectors for ex vivo delivery of the gene are retroviral and lentiviral vectors. Preferred in vivo nucleic acid transfer techniques include transfection with viral 15 vectors such as adenovirus, Herpes simplex I virus, adeno-associated virus), lipid-based systems (useful lipids for lipid-mediated transfer of the gene are DOTMA, DOPE and DC-Chol, for example), naked DNA, and transposon-based expression systems. For review of the currently known gene marking and gene therapy protocols see Anderson et al., Science 256:808-813 (1992). See also WO 93 / 25673 and the references cited therein. 20          “Gene therapy” includes both conventional gene therapy where a lasting effect is achieved by a single treatment, and the administration of gene therapeutic agents, which involves the one time or repeated administration of a therapeutically effective DNA or mRNA. Oligonucleotides can be modified to enhance their uptake, e.g. by substituting their negatively charged phosphodiester groups by uncharged groups. Fusion proteins of the 25 present invention can be delivered using gene therapy methods, for example locally in tumor beds, intrathecally, or systemically (e.g., via vectors that selectively target specific tissue types, for example, tissue-specific adeno-associated viral vectors). In some embodiments, primary cells (such as lymphocytes or stem cells) from the individual can be transfected ex vivo with a gene encoding any of the fusion proteins of the present invention, and then 30 returning the transfected cells to the individual's body. “Treating” or “treatment” refers to therapeutic treatment, wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder. A subject is successfully “treated” if: after receiving a therapeutic amount of a fusion protein of the invention according to the methods of the present invention, the subject shows observable 2026204884   23 Jun 2026 and / or measurable reduction in or absence of one or more signs and symptoms of the particular disease. For example, for cancer, reduction in the number of cancer cells or absence of the cancer cells; reduction in the tumor size; inhibition (i.e., slow to some extent and preferably stop) of tumor metastasis; inhibition, to some extent, of tumor growth; 5 increase in length of remission, and / or relief to some extent, one or more of the symptoms associated with the specific cancer; reduced morbidity and mortality, and improvement in quality of life issues. Reduction of the signs or symptoms of a disease may also be felt by the patient. Treatment can achieve a complete response, defined as disappearance of all signs of cancer, or a partial response, wherein the size of the tumor is decreased, preferably by more 10 than 50%, more preferably by 75%. A patient is also considered treated if the patient experiences a stabilization of disease. These parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician of appropriate skill in the art. In the context of treatment for cancer, the fusion proteins of the present invention can 15 optionally be administered to a patient in combination with other chemotherapeutic agents. Suitable chemotherapeutic agents include, for example, alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN™); alkyl sulfonates such as busulfan, improsiilfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, 20 trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as 25 aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, 30 tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, 2026204884   23 Jun 2026 dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium 5 acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK.R™; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); 10 cyclophosphamide; thiotepa; taxanes, e.g. paclitaxel (TAXOL.R™, Bristol-Myers Squibb Oncology, Princeton, N.J.) and docetaxel (TAXOTERE.R™, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); Ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; 15 teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoic acid; esperamicins; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Other chemotherapeutic agents further include anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens including for example 20 tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Other tumor cytotoxic agents that can be used in combination with a fusion protein of 25 the invention are themselves fusion proteins. Exemplars of tumor cytotoxic fusion proteins are CTLA-4-FasL and Fnl4-TRAIL, which, as cis loop-back proteins, can act by creating auto-apoptotic signaling loops at the surface of tumor cells. See U.S. Patent Nos 7,569,663; 8,329,657 and 8,039,437, each of which is incorporated by reference in its entirety. In turn, those cis loop-back proteins incorporating a TRAIL component can be administered in 30 combination with chemotherapeutic agents that are able to sensitize tumor cells to TRAIL and overcome TRAIL resistance, such as proteasome inhibitors and histone deacetylase (HDAC) inhibitors, cycloheximide, imatinib mesylate and other protein tyrosine kinase inhibitors, 17-allylamino-17-demethoxygeldanamycin, arsenic trioxide andX-linked Inhibitors of Apoptosis Protein small molecule antagonists; and pharmaceutically acceptable 2026204884   23 Jun 2026 salts, acids or derivatives of any of these. Additional information on the methods of cancer treatment is provided in U.S. Pat. No. 7,285,522, incorporated by reference in its entirety. The practice of the invention is illustrated by the following non-limiting examples. 5 The invention should not be construed to be limited solely to the compositions and methods described herein, but should be construed to include other compositions and methods as well. One of skill in the art will know that other compositions and methods are available to perform the procedures described herein. The practice of the present invention employs, unless otherwise indicated, 10 conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are well within the purview of the skilled artisan. Such techniques are explained fully in the literature, such as, “Molecular Cloning: A Laboratory Manual”, fourth edition (Sambrook, 2012); “Oligonucleotide Synthesis” (Gait, 1984); “Culture of Animal Cells” (Freshney, 2010); 15 “Methods in Enzymology” “Handbook of Experimental Immunology” (Weir, 1997); “Gene Transfer Vectors for Mammalian Cells” (Miller and Calos, 1987); “Short Protocols in Molecular Biology” (Ausubel, 2002); “Polymerase Chain Reaction: Principles, Applications and Troubleshooting”, (Babar, 2011); “Current Protocols in Immunology” (Coligan, 2002). These techniques are applicable to the production of the polynucleotides and polypeptides of 20 the invention, and, as such, may be considered in making and practicing the invention. Particularly useful techniques for particular embodiments will be discussed in the sections that follow. 25                      EXPERIMENTAL EXAMPLES The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only, and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any 30 and all variations which become evident as a result of the teaching provided herein. Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. The following working examples therefore, specifically point out the preferred embodiments of the present 2026204884   23 Jun 2026 invention, and are not to be construed as limiting in any way the remainder of the disclosure. Example 1-Fusion Protein Binding Fusion protein constructs and expression. 5 The expression plasmid constructs for these fusion proteins were generated using gene fragments synthesized de novo (ThermoFisher Scientific) for each of the desired ligand / receptor components, linked to synthesized gene fragments of the hinge, CH2 and CH3 domains of either the A or B chains (i.e. Z2,    Z2’ or Z3’ domains). The individual components were spliced together by polymerase chain reaction (PCR) using primers at the 10 ends containing restriction sites for cloning into the expression plasmid, pCEP4, an EBV episomal expression vector (originally developed in the Tykocinski laboratory) that replicates extra-chromosomally at high copy numbers. At the time of gene synthesis, the DNA fragments are codon optimized for expression in Chinese hamster ovary suspension (CHO-S) cells. Fusion proteins were produced by transient co-transfection of an A chain construct and 15 a B chain construct into ExpiCHO-S shake flask cultures using TransIT-Pro reagent (MIRUS) at 37° C for 24 h, then incubated at 32° C for 8-10 total days. Proteins were purified from conditioned culture supernatant by mixing with Protein A agarose resin at 6° C overnight and then collected and eluted with a non-denaturing neutral pH elution buffer (PIERCE). Each fusion protein was verified by sodium dodecyl sulfate polyacrylamide gel 20 electrophoresis (SDS-PAGE) for size and integrity. Fusion protein binding studies. Ligand constructs expressing the full-length cDNA for human CD155, T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), CD112 and CD 16 25 (FcyRIIIa) were generated by PCR and cloned into the expression plasmid pcDNA3.1+ (ThermoFisher Scientific). Each expression construct was transfected into CHO-S cells with Lipofectamine 3000 (ThermoFisher) and stable transfectants selected by the addition of G418. Ligand expression was determined by flow cytometry following immunostaining with the appropriate fluorochrome-conjugated anti-ligand antibody (black line) or the appropriate 30 fluorochrome-conjugated isotype control antibody (gray line and fill). Data were analyzed using FCSalyzer software. For fusion protein binding studies, fusion proteins were added to either non-transfected CHO-S cells as control (gray line and fill) or CHO-S transfectants expressing corresponding ligands and incubated for 1 h at 6° C, then washed, and 2026204884   23 Jun 2026 immunostained with Cy5-conjugated anti-human IgG, Fcy-specific antibody (black line) and analyzed by flow cytometry. See Figures 18-20. For CD16 binding studies, TIGIT or CD155 containing fusion proteins were incubated with either non-transfected CHO-S cells as control (gray line and fill) or CD16-expressing CHO-S transfectants and detected by immunostaining 5 with APC- or PE-conjugated antibody recognizing TIGIT or CD155, respectively (black line). See Figure 21. Example 2-Fusion Protein Binding Assays and Migration Assays Protein gel analysis 10 Fusion Proteins were separated and reduced (R) or non-reduced (NR) on 12% SDS-PAGE gel and stained for 12 hours in PageBlue Protein Staining Solution (Thermo Scientific). See Figure 22. Immunoblot analysis 15 Fusion proteins were then quantitated by Pierce BCA Protein Assay Kit (Thermo Fisher) and loaded on 12% SDS-PAGE gels. Proteins were electrotransferred onto Immobilon-P membranes (EMD Millipore, Billerica, MA) and incubated with (A) Ab against PD1 and (B) Ab against IgG light chain primary antibodies for 12 h in Odyssey blocking buffer (Licor, Lincoln, NE). The corresponding secondary antibodies were used at 1:10,000 dilutions (Santa 20 Cruz). Immunoblots were scanned using the Odyssey Infrared Imaging System (LI-COR Biosciences, model #9120). See Figure 23. Fusion protein binding studies. CXCR4 / 7 and PD1+ melanoma cell lines, (A) YUMMER1.7 cells or (B) Bl6, were 25 incubated with the indicated fusion proteins for 1 h at 6° C, then washed, and immunostained with Cy5-conjugated anti-human IgG, Fcy-specific antibody and analyzed by flow cytometry (solid black line), control sample incubated without fusion protein (filled grey line) as shown in Figure 24. 30 Transwell Assay. Transwell inserts were inserted in 24-well companion plates (Coming, cat. #353504). Cell suspensions were seeded in top invasion chambers at 25,000 cells / chamber. DMEM with lOOng / mL of CXCL12 was added to each bottom well as chemoattractant. Samples were 2026204884   23 Jun 2026 incubated at 37°C for 24 hours to allow for cell migration. Non-invading cells on the apical surface of the insert were removed with cotton swabs, and cells that had migrated to the lower surface of the supports were stained using 2% crystal violet. See Figure 25. 5 Example 3- TriTouch-101 induces melanoma regression Inhibition of tumor growth was induced by TriTouch-101 PDlhFcA*vMIPIICH-hFcB*CL (FP) in vivo, The B16F10 melanoma subcutaneous model was used to demonstrate the induction of melanoma regression by PDlhFcA*vMIPIICH-hFcB*CL (FP). Briefly, BL16 mice were treated with 100 pl of (lOug / mL) FP (mice R, 2L and 2R) or PBS (Mice X 10 or L), 5 times on days 13, 14, 15, 16 and 21 days post-subcutaneously inoculated with 1 x 105 Bl6F10 cells. Tumor sizes were measured (Figure 26A). Representative images of 1 mouse from each treatment group, (X top and 2R bottom) are depicted in Figure 26B. These in vivo data showing TriTouch-101 induces melanoma regression, go along with previous data showing that this fusion protein inhibits melanoma cells in a migration assay (Figure 25) 15     . Example 4- NK modulating TriTouch protein species ADCC was augmented by addition of multi-functional fusion proteins (Figure 27). The SKOV-3 ovarian cell line was plated in a 96-well plate at 3000 cells / well, allowed to 20 adhere and labeled with CellTracker Red CMTPX reagent. The SKOV-3 cells were then labeled with a green fluorescence Caspase-3 reagent. The CD16.NK-92 cell line (V158 variant) was added to the wells at a E:T 5:1 with the various fusion proteins at 25 mg / ml or no protein and analyzed using the Incucyte live-cell analysis system, measuring the number of fluorescent double positive (red + green) cells . Results shown depict the 20 h time point 25 (Figure 27). Other Embodiments The recitation of a listing of elements in any definition of a variable herein includes definitions of that variable as any single element or combination (or subcombination) of 30 listed elements. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiment or portions thereof. The disclosures of each and every’ patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments 2026204884   23 Jun 2026 and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations. 5 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference in this specification to any prior publication (or information derived from it), or 10 to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims

1. A fusion protein comprising Component A, Component B, and Component C; wherein:Component A comprises the amino acid sequence of any one of SEQ ID NOs: 14-15,Component B comprises the amino acid sequence of any one of SEQ ID NOs: 49-55, andComponent C comprises the amino acid sequence of any one of SEQ ID NO: 57-63.

2. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and thefusion protein of claim 1.

3. The fusion protein of claim 1 for use in treating a proliferative disorder in a patient inneed of such treatment.

4. The fusion protein for use of claim 3, wherein the proliferative disorder is cancer.

5. The fusion protein for use of claim 4, wherein the cancer is a solid tumor.

6. The fusion protein for use of claim 4, wherein the cancer is pancreatic cancer, breastcancer, ovarian cancer, bladder cancer, melanoma, glioblastoma, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), multiple myeloma or colon cancer.

7. A method for treating a proliferative disorder in a patient in need of such treatment,comprising administering to the patient the fusion protein of claim 1 or the pharmaceutical composition of claim 2.

8. Use of the fusion protein of claim 1 in the preparation of a medicament for the treatmentof a proliferative disorder in a patient.

9. The method of claim 7 or the use of claim 8, wherein the proliferative disorder is cancer.

10. The method or use of claim 9, wherein the cancer is a solid tumor.2026204884   23 Jun 202611. The method or use of claim 9, wherein the cancer is pancreatic cancer, breast cancer, ovarian cancer, bladder cancer, melanoma, glioblastoma, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), multiple myeloma or colon cancer.

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