HRP20221323T1 - Protutijela protiv signalno-regulacijskog proteina alfa i postupci njihove uporabe - Google Patents

Protutijela protiv signalno-regulacijskog proteina alfa i postupci njihove uporabe Download PDF

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HRP20221323T1
HRP20221323T1 HRP20221323TT HRP20221323T HRP20221323T1 HR P20221323 T1 HRP20221323 T1 HR P20221323T1 HR P20221323T T HRP20221323T T HR P20221323TT HR P20221323 T HRP20221323 T HR P20221323T HR P20221323 T1 HRP20221323 T1 HR P20221323T1
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Croatia
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seq
amino acid
acid sequence
sequence
hvr
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HRP20221323TT
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Jaume Pons
Bang Janet Sim
Hong Wan
Tracy Chia-Chien Kuo
Steven Elliot KAUDER
William Don Harriman
Shelley IZQUIERDO
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ALX Oncology Inc.
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Publication of HRP20221323T1 publication Critical patent/HRP20221323T1/hr

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Claims (20)

1. Izolirano protutijelo koje se veže na izvanstaničnu domenu ljudskog polipeptida SIRP-α, pri čemu se protutijelo veže na izvanstaničnu domenu ljudskog polipeptida SIRP-α v1, izvanstaničnu domenu ljudskog polipeptida SIRP-α v2, izvanstaničnu domenu majmunskog polipeptida SIRP-α, te izvanstaničnu domenu mišjeg polipeptida SIRP-α; i pri čemu protutijelo sadrži: (a) varijabilnu domenu teškog lanca (VH), koja sadrži: (i) HVR-H1 slijed koji sadrži aminokiselinski slijed X1X2AX3S, pri čemu je X1 S ili T; X2 je N, Y, H ili D; i X3 je M, L ili V (SEQ ID NO:297); (ii) HVR-H2 slijed koji sadrži aminokiselinski slijed GISX1X2X3X4X5X6YYX7X8SX9KG, pri čemu je X1 A ili S; X2 je G, S, ili je odsutan; X3 je S, D ili G; X4 je G ili S; X5 je D, S ili G; X6 je T ili A; X7 je P, G, V, I, A ili S; X8 je A, D ili G; i X9 je V ili M (SEQ ID NO:298); i (iii) HVR-H3 slijed koji sadrži aminokiselinski slijed ETWNHLFDY (SEQ ID NO:193); i (b) varijabilnu domenu lakog lanca (VL), koja sadrži: (i) HVR-L1 slijed koji sadrži aminokiselinski slijed SGGX1X2X3SX4YYX5, pri čemu je X1 D, G, S, I, ili je odsutan; X2 je S, W, G, Y, D, ili je odsutan; X3 je S, Y, T ili D; X4 je H, T, S ili Y; i X5 je G ili A (SEQ ID NO:299); (ii) HVR-L2 slijed koji sadrži aminokiselinski slijed SDX1X2RPX3, pri čemu je X1 D ili N; X2 je E, K ili Q; i X3 je S ili P (SEQ ID NO:300); i (iii) HVR-L3 slijed koji sadrži aminokiselinski slijed X1X2YDX3X4X5YX6NX7, pri čemu je X1 G ili A; X2 je G ili A; X3 je G, Y, Q, S ili A; X4 je S, R ili T; X5 je T ili S; X6 je A, I, V, L ili T; i X7 je T, A, D ili P (SEQ ID NO:301).
2. Protutijelo u skladu s patentnim zahtjevom 1, pri čemu je protutijelo humanizirano protutijelo kojeg proizvodi ili ga se dobiva iz kokoši.
3. Protutijelo u skladu s patentnim zahtjevom 1 ili 2, pri čemu protutijelo blokira vezanje između izvanstanične domene ljudskog polipeptida SIRP-α i domene IgSF ljudskog polipeptida CD47.
4. Protutijelo u skladu s patentnim zahtjevom 1 ili 2, pri čemu protutijelo sadrži: (a) varijabilnu domenu teškog lanca (VH), koja sadrži: (i) HVR-H1 slijed koji sadrži aminokiselinski slijed SX1AX2S, pri čemu je X1 N ili Y; i pri čemu X2 je M, L ili V (SEQ ID NO:302); (ii) HVR-H2 slijed koji sadrži aminokiselinski slijed GISX1GX2X3DTYYX4X5SVKG, pri čemu je X1 A ili S; X2 je G ili je odsutan; X3 je S ili G; X4 je P, G ili V; i X5 je A ili D (SEQ ID NO:303); i (iii) HVR-H3 slijed koji sadrži aminokiselinski slijed ETWNHLFDY (SEQ ID NO:193); i (b) varijabilnu domenu lakog lanca (VL), koja sadrži: (i) HVR-L1 slijed koji sadrži aminokiselinski slijed SGGX1YSSYYYA, pri čemu je X1 S ili A (SEQ ID NO:304); (ii) HVR-L2 slijed koji sadrži aminokiselinski slijed SDDKRPS (SEQ ID NO:336); i (iii) HVR-L3 slijed koji sadrži aminokiselinski slijed GGYDQSSYTNP (SEQ ID NO:172).
5. Protutijelo u skladu s patentnim zahtjevom 4, pri čemu VH domena sadrži: (a) (i) HVR-H1 slijed koji sadrži aminokiselinski slijed SNAMS (SEQ ID NO:194), SNAVS (SEQ ID NO:271) ili SNALS (SEQ ID NO:318), (ii) HVR-H2 slijed koji sadrži aminokiselinski slijed GISAGGSDTYYPASVKG (SEQ ID NO:195), te (iii) HVR-H3 slijed koji sadrži aminokiselinski slijed ETWNHLFDY (SEQ ID NO:193); (b) aminokiselinski slijed koji je najmanje 90 % istovjetan aminokiselinskom slijedu SEQ ID NO:135, 263, 264 ili 330; (c) (i) HVR-H1 slijed koji sadrži aminokiselinski slijed SNAMS (SEQ ID NO:194), SNAVS (SEQ ID NO:271) ili SNALS (SEQ ID NO:318), (ii) HVR-H2 slijed koji sadrži aminokiselinski slijed GISSGSDTYYGDSVKG (SEQ ID NO:197), te (iii) HVR-H3 slijed koji sadrži aminokiselinski slijed ETWNHLFDY (SEQ ID NO:193); (d) aminokiselinski slijed koji je najmanje 90 % istovjetan aminokiselinskom slijedu SEQ ID NO:137, 265, 266 ili 331; (e) (i) HVR-H1 slijed koji sadrži aminokiselinski slijed SYAMS (SEQ ID NO:200), SYAVS (SEQ ID NO:272) ili SYALS (SEQ ID NO:319), (ii) HVR-H2 slijed koji sadrži aminokiselinski slijed GISSGGDTYYVDSVKG (SEQ ID NO:201), te (iii) HVR-H3 slijed koji sadrži aminokiselinski slijed ETWNHLFDY (SEQ ID NO:193); ili (f) aminokiselinski slijed koji je najmanje 90 % istovjetan aminokiselinskom slijedu SEQ ID NO:139, 267, 268 ili 332.
6. Protutijelo u skladu s bilo kojim od patentnih zahtjeva 4-5, pri čemu VL domena sadrži: (a) (i) HVR-L1 slijed koji sadrži aminokiselinski slijed SGGSYSSYYYA (SEQ ID NO:170), (ii) HVR-L2 slijed koji sadrži aminokiselinski slijed SDDKRPS (SEQ ID NO:336), te (iii) HVR-L3 slijed koji sadrži aminokiselinski slijed GGYDQSSYTNP (SEQ ID NO:172); (b) aminokiselinski slijed koji je najmanje 90 % istovjetan aminokiselinskom slijedu SEQ ID NO:252; (c) (i) HVR-L1 slijed koji sadrži aminokiselinski slijed SGGAYSSYYYA (SEQ ID NO:261), (ii) HVR-L2 slijed koji sadrži aminokiselinski slijed SDDKRPS (SEQ ID NO:336), te (iii) HVR-L3 slijed koji sadrži aminokiselinski slijed GGYDQSSYTNP (SEQ ID NO:172); ili (d) aminokiselinski slijed koji je najmanje 90 % istovjetan aminokiselinskom slijedu SEQ ID NO:262; pri čemu VL domena može sadržavati slijed FW1—HVR-L1—FW2—HVR-L2—FW3—HVR-L3—FW4 (od N-kraja do C-kraja), pri čemu FW1 sadrži aminokiselinski slijed SYELTQPPSVSVSPGQTARITC (SEQ ID NO:314), FW2 sadrži aminokiselinski slijed WYQQKPGQAPVTLIY (SEQ ID NO:315), FW3 sadrži aminokiselinski slijed NIPERFSGSSSGTTVTLTISGVQAEDEADYYC (SEQ ID NO:316), te FW4 sadrži aminokiselinski slijed FGGGTKLTVL (SEQ ID NO:317); i pri čemu protutijelo može sadržavati konstantno područje lakog lanca koje sadrži aminokiselinski slijed SEQ ID NO:325, 326 ili 426.
7. Protutijelo u skladu s patentnim zahtjevom 4, pri čemu (a) VH domena sadrži (i) HVR-H1 slijed koji sadrži aminokiselinski slijed SNAMS (SEQ ID NO:194), SNAVS (SEQ ID NO:271) ili SNALS (SEQ ID NO:318), (ii) HVR-H2 slijed koji sadrži aminokiselinski slijed GISAGGSDTYYPASVKG (SEQ ID NO:195), te (iii) HVR-H3 slijed koji sadrži aminokiselinski slijed ETWNHLFDY (SEQ ID NO:193), a VL domena sadrži (iv) HVR-L1 slijed koji sadrži aminokiselinski slijed SGGSYSSYYYA (SEQ ID NO:170), (v) HVR-L2 slijed koji sadrži aminokiselinski slijed SDDKRPS (SEQ ID NO:336), te (vi) HVR-L3 slijed koji sadrži aminokiselinski slijed GGYDQSSYTNP (SEQ ID NO:172); (b) VH domena sadrži (i) HVR-H1 slijed koji sadrži aminokiselinski slijed SNAMS (SEQ ID NO:194), SNAVS (SEQ ID NO:271) ili SNALS (SEQ ID NO:318), (ii) HVR-H2 slijed koji sadrži aminokiselinski slijed GISSGSDTYYGDSVKG (SEQ ID NO:197), te (iii) HVR-H3 slijed koji sadrži aminokiselinski slijed ETWNHLFDY (SEQ ID NO:193), a VL domena sadrži (iv) HVR-L1 slijed koji sadrži aminokiselinski slijed SGGSYSSYYYA (SEQ ID NO:170), (v) HVR-L2 slijed koji sadrži aminokiselinski slijed SDDKRPS (SEQ ID NO:336), te (vi) HVR-L3 slijed koji sadrži aminokiselinski slijed GGYDQSSYTNP (SEQ ID NO:172); (c) VH domena sadrži (i) HVR-H1 slijed koji sadrži aminokiselinski slijed SYAMS (SEQ ID NO:200), SYAVS (SEQ ID NO:272) ili SYALS (SEQ ID NO:319), (ii) HVR-H2 slijed koji sadrži aminokiselinski slijed GISSGGDTYYVDSVKG (SEQ ID NO:201), te (iii) HVR-H3 slijed koji sadrži aminokiselinski slijed ETWNHLFDY (SEQ ID NO:193), a VL domena sadrži (iv) HVR-L1 slijed koji sadrži aminokiselinski slijed SGGSYSSYYYA (SEQ ID NO:170), (v) HVR-L2 slijed koji sadrži aminokiselinski slijed SDDKRPS (SEQ ID NO:336), te (vi) HVR-L3 slijed koji sadrži aminokiselinski slijed GGYDQSSYTNP (SEQ ID NO:172); (d) VH domena sadrži (i) HVR-H1 slijed koji sadrži aminokiselinski slijed SNAMS (SEQ ID NO:194), SNAVS (SEQ ID NO:271) ili SNALS (SEQ ID NO:318), (ii) HVR-H2 slijed koji sadrži aminokiselinski slijed GISAGGSDTYYPASVKG (SEQ ID NO:195), te (iii) HVR-H3 slijed koji sadrži aminokiselinski slijed ETWNHLFDY (SEQ ID NO:193), a VL domena sadrži (iv) HVR-L1 slijed koji sadrži aminokiselinski slijed SGGAYSSYYYA (SEQ ID NO:261), (v) HVR-L2 slijed koji sadrži aminokiselinski slijed SDDKRPS (SEQ ID NO:336), te (vi) HVR-L3 slijed koji sadrži aminokiselinski slijed GGYDQSSYTNP (SEQ ID NO:172); (e) VH domena sadrži (i) HVR-H1 slijed koji sadrži aminokiselinski slijed SNAMS (SEQ ID NO:194), SNAVS (SEQ ID NO:271) ili SNALS (SEQ ID NO:318), (ii) HVR-H2 slijed koji sadrži aminokiselinski slijed GISSGSDTYYGDSVKG (SEQ ID NO:197), te (iii) HVR-H3 slijed koji sadrži aminokiselinski slijed ETWNHLFDY (SEQ ID NO:193), a VL domena sadrži (iv) HVR-L1 slijed koji sadrži aminokiselinski slijed SGGAYSSYYYA (SEQ ID NO:261), (v) HVR-L2 slijed koji sadrži aminokiselinski slijed SDDKRPS (SEQ ID NO:336), te (vi) HVR-L3 slijed koji sadrži aminokiselinski slijed GGYDQSSYTNP (SEQ ID NO:172); ili (f) VH domena sadrži (i) HVR-H1 slijed koji sadrži aminokiselinski slijed SYAMS (SEQ ID NO:200), SYAVS (SEQ ID NO:272) ili SYALS (SEQ ID NO:319), (ii) HVR-H2 slijed koji sadrži aminokiselinski slijed GISSGGDTYYVDSVKG (SEQ ID NO:201), te (iii) HVR-H3 slijed koji sadrži aminokiselinski slijed ETWNHLFDY (SEQ ID NO:193), a VL domena sadrži (iv) HVR-L1 slijed koji sadrži aminokiselinski slijed SGGAYSSYYYA (SEQ ID NO:261), (v) HVR-L2 slijed koji sadrži aminokiselinski slijed SDDKRPS (SEQ ID NO:336), te (vi) HVR-L3 slijed koji sadrži aminokiselinski slijed GGYDQSSYTNP (SEQ ID NO:172).
8. Protutijelo u skladu s patentnim zahtjevom 1, pri čemu (a) VH domena sadrži aminokiselinski slijed SEQ ID NO:263, a VL domena sadrži aminokiselinski slijed SEQ ID NO:252; (b) VH domena sadrži aminokiselinski slijed SEQ ID NO:264, a VL domena sadrži aminokiselinski slijed SEQ ID NO:252; (c) VH domena sadrži aminokiselinski slijed SEQ ID NO:330, a VL domena sadrži aminokiselinski slijed SEQ ID NO:252; (d) VH domena sadrži aminokiselinski slijed SEQ ID NO:135, a VL domena sadrži aminokiselinski slijed SEQ ID NO:252; (e) VH domena sadrži aminokiselinski slijed SEQ ID NO:137, a VL domena sadrži aminokiselinski slijed SEQ ID NO:252; (f) VH domena sadrži aminokiselinski slijed SEQ ID NO:139, a VL domena sadrži aminokiselinski slijed SEQ ID NO:252; (g) VH domena sadrži aminokiselinski slijed SEQ ID NO:265, a VL domena sadrži aminokiselinski slijed SEQ ID NO:252; (h) VH domena sadrži aminokiselinski slijed SEQ ID NO:266, a VL domena sadrži aminokiselinski slijed SEQ ID NO:252; (i) VH domena sadrži aminokiselinski slijed SEQ ID NO:331, a VL domena sadrži aminokiselinski slijed SEQ ID NO:252; (j) VH domena sadrži aminokiselinski slijed SEQ ID NO:267, a VL domena sadrži aminokiselinski slijed SEQ ID NO:252; (k) VH domena sadrži aminokiselinski slijed SEQ ID NO:268, a VL domena sadrži aminokiselinski slijed SEQ ID NO:252; (l) VH domena sadrži aminokiselinski slijed SEQ ID NO:332, a VL domena sadrži aminokiselinski slijed SEQ ID NO:252; (j) VH domena sadrži aminokiselinski slijed SEQ ID NO:263, a VL domena sadrži aminokiselinski slijed SEQ ID NO:262; (m) VH domena sadrži aminokiselinski slijed SEQ ID NO:264, a VL domena sadrži aminokiselinski slijed SEQ ID NO:262; (n) VH domena sadrži aminokiselinski slijed SEQ ID NO:330, a VL domena sadrži aminokiselinski slijed SEQ ID NO:262; (o) VH domena sadrži aminokiselinski slijed SEQ ID NO:265, a VL domena sadrži aminokiselinski slijed SEQ ID NO:262; (p) VH domena sadrži aminokiselinski slijed SEQ ID NO:266, a VL domena sadrži aminokiselinski slijed SEQ ID NO:262; (q) VH domena sadrži aminokiselinski slijed SEQ ID NO:331, a VL domena sadrži aminokiselinski slijed SEQ ID NO:262; (r) VH domena sadrži aminokiselinski slijed SEQ ID NO:267, a VL domena sadrži aminokiselinski slijed SEQ ID NO:262; (s) VH domena sadrži aminokiselinski slijed SEQ ID NO:268, a VL domena sadrži aminokiselinski slijed SEQ ID NO:262; (t) VH domena sadrži aminokiselinski slijed SEQ ID NO:332, a VL domena sadrži aminokiselinski slijed SEQ ID NO:262; (u) VH domena sadrži aminokiselinski slijed SEQ ID NO:135, a VL domena sadrži aminokiselinski slijed SEQ ID NO:262; (v) VH domena sadrži aminokiselinski slijed SEQ ID NO:137, a VL domena sadrži aminokiselinski slijed SEQ ID NO:262; ili (w) VH domena sadrži aminokiselinski slijed SEQ ID NO:139, a VL domena sadrži aminokiselinski slijed SEQ ID NO:262.
9. Protutijelo u skladu s patentnim zahtjevom 1 ili 2, pri čemu se protutijelo veže na ljudski polipeptid SIRP-α v1 na jednom ili više aminokiselinskih položaja koje se bira iz skupine koju čine I31, V33, Q52, K53, T67, R69, N70, te K96, prema SEQ ID NO:296; pri čemu izborno: (a) protutijelo se veže na ljudski polipeptid SIRP-α v1 na I31, V33, Q52, K53, T67, R69, N70, te K96, prema SEQ ID NO:296; (b) protutijelo se dodatno veže na ljudski polipeptid SIRP-α v1 na jednom ili više aminokiselinskih položaja koje se bira iz skupine koju čine L30, P32, E54, T62, N71, M72, F74, te R95, prema SEQ ID NO:296; (c) protutijelo se dodatno veže na ljudski polipeptid SIRP-α v1 na L30, P32, E54, T62, N71, M72, F74, te R95, prema SEQ ID NO:296; i/ili (d) ljudski polipeptid SIRP-α v1 sadrži aminokiselinski slijed SEQ ID NO:5, ljudski polipeptid SIRP-α v2 sadrži aminokiselinski slijed SEQ ID NO:6, majmunski polipeptid SIRP-α sadrži aminokiselinski slijed SEQ ID NO:11, a mišji polipeptid SIRP-α sadrži aminokiselinski slijed SEQ ID NO: 7.
10. Protutijelo u skladu s bilo kojim od patentnih zahtjeva 1-9, pri čemu je protutijelo: (a) monoklonsko protutijelo; ili (b) scFv-Fc protutijelo.
11. Protutijelo u skladu s bilo kojim od patentnih zahtjeva 1-9, pri čemu protutijelo sadrži Fc područje; pri čemu izborno: (a) protutijelo sadrži aminokiselinski slijed kojeg se bira iz skupine koju čine SEQ ID NO:320-324; (b) Fc područje je ljudsko Fc područje kojeg se bira iz skupine koju čine Fc područje iz IgG1, Fc područje iz IgG2, te Fc područje iz IgG4; (c) Fc područje uključuje Fc područje ljudskog IgG1 koje sadrži jednu ili više mutacija koje se bira iz skupine koju čine L234A, L235A, G237A, te N297A, prema EU obrojčavanju; (d) Fc područje uključuje Fc područje ljudskog IgG2 koje sadrži jednu ili više mutacija koje se bira iz skupine koju čine A330S, P331S i N297A, prema EU obrojčavanju; (e) Fc područje uključuje Fc područje ljudskog IgG2 koje sadrži mutaciju N297A, prema EU obrojčavanju; (f) Fc područje uključuje Fc područje ljudskog IgG2 koje sadrži mutaciju A330S i/ili P331S, prema EU obrojčavanju; ili (g) Fc područje uključuje Fc područje ljudskog IgG4 koje sadrži jednu ili više mutacija koje se bira iz skupine koju čine S228P, E233P, F234V, L235A, L235E, delG236, te N297A, prema EU obrojčavanju.
12. Protutijelo u skladu s patentnim zahtjevom 1, pri čemu VH domena sadrži aminokiselinski slijed SEQ ID NO: 263, a VL domena sadrži aminokiselinski slijed SEQ ID NO: 252; pri čemu protutijelo dodatno sadrži konstantno područje lakog lanca koje sadrži aminokiselinski slijed SEQ ID NO: 325, 326 ili 426; i pri čemu protutijelo dodatno sadrži aminokiselinski slijed kojeg se bira iz skupine koju čine SEQ ID NO:320-324.
13. Protutijelo u skladu s bilo kojim od patentnih zahtjeva 1-12, pri čemu: (a) protutijelo je konjugirano s citotoksičnim sredstvom ili biljegom; ili (b) protutijelo je bispecifično protutijelo.
14. Jedan ili više polinukleotida koji kodiraju protutijelo u skladu s bilo kojim od patentnih zahtjeva 1-13.
15. Jedan ili više vektora koji sadrže polinukleotide u skladu s patentnim zahtjevom 14.
16. Jedan ili više stanica domaćina koje sadrže polinukleotide u skladu s patentnim zahtjevom 14 ili vektore u skladu s patentnim zahtjevom 15.
17. Postupak proizvodnje protutijela, gdje se postupak sastoji u uzgoju stanica domaćina u skladu s patentnim zahtjevom 16 na takav način da se proizvodi protutijelo; pri čemu postupak može dodatno uključivati prikupljanje protutijela iz stanice domaćina.
18. Farmaceutski pripravak koji sadrži protutijelo u skladu s bilo kojim od patentnih zahtjeva 1-13 i farmaceutski prihvatljivi nosač.
19. Protutijelo u skladu s bilo kojim od patentnih zahtjeva 1-13, namijenjeno uporabi u (a) postupku liječenja ili odgađanja napredovanja raka kod osobe ili (b) postupku liječenja ili odgađanja napredovanja autoimune bolesti ili upalne bolesti kod osobe, gdje se postupak sastoji u primjeni na osobi djelotvorne količine protutijela.
20. Protutijelo namijenjeno uporabi u skladu s patentnim zahtjevom 19(a), pri čemu postupak dodatno uključuje primjenu na osobi: (a) djelotvorna količina drugog protutijela koje se veže na antigen kojeg eksprimira rak, pri čemu se antigen kojeg eksprimira rak može birati iz skupine koju čine CD19, CD20, CD22, CD30, CD33, CD38, CD52, CD56, CD70, CD74, CD79b, CD123, CD138, CS1/SLAMF7, Trop-2, 5T4, EphA4, BCMA, mucin 1, mucin 16, PTK7, STEAP1, receptor endotelina B, mezotelin, EGFRvIII, ENPP3, SLC44A4, GNMB, nektin 4, NaPi2b, LIV-1A, gvanilil-ciklaza C, DLL3, EGFR, HER2, VEGF, VEGFR, integrin αVβ3, integrin α5β1, MET, IGF1R, TRAILR1, TRAILR2, RANKL, FAP, tenascin, Ley, EpCAM, CEA, gpA33, PSMA, TAG72, mucin, CAIX, EPHA3, folatni receptor α, GD2, GD3, te MHC/peptidni kompleks koji sadrži peptid iz NY-ESO-1/LAGE, SSX-2, protein iz porodice MAGE, MAGE-A3, gp100/pmel17, Melan-A/MART-1, gp75/TRP1, tirozinaza, TRP2, CEA, PSA, TAG-72, nezreli lamininski receptor, MOK/RAGE-1, WT-1, SAP-1, BING-4, EpCAM, MUC1, PRAME, survivin, BRCA1, BRCA2, CDK4, CML66, MART-2, p53, Ras, β-katenin, TGF-βRII, HPV E6 ili HPV E7; ili (b) djelotvorna količina imunoterapijskog sredstva, pri čemu izborno imunoterapijsko sredstvo sadrži drugo protutijelo, te pri čemu se drugo protutijelo može vezati na antigen kojeg se bira iz skupine koju čine PD-1, PD-L1, OX40, CTLA-4, CD137/4-1BB, TNFR2, B7-H3, FZD7, CD27, CCR4, CSF1R, CSF, TIM-3, LAG-3, VISTA, ICOS, CCR2, IDO, A2R, CD39, CD73, TIGIT, CD80, CD47, arginaza, TDO, te PVRIG.
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