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HRP20210739T1 - Molekule koje vežu antigen i sadrže trimer obitelji tnf liganada - Google Patents

Molekule koje vežu antigen i sadrže trimer obitelji tnf liganada Download PDF

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Publication number
HRP20210739T1
HRP20210739T1 HRP20210739TT HRP20210739T HRP20210739T1 HR P20210739 T1 HRP20210739 T1 HR P20210739T1 HR P20210739T T HRP20210739T T HR P20210739TT HR P20210739 T HRP20210739 T HR P20210739T HR P20210739 T1 HRP20210739 T1 HR P20210739T1
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seq
amino acid
acid sequence
antigen
domain
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HRP20210739TT
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Maria AMANN
Peter Bruenker
Christina CLAUS
Claudia Ferrara Koller
Sandra GRAU-RICHARDS
Christian Klein
Viktor LEVITSKI
Ekkehard Moessner
Joerg Thomas Regula
Pablo Umaña
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F. Hoffmann - La Roche Ag
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Application filed by F. Hoffmann - La Roche Ag filed Critical F. Hoffmann - La Roche Ag
Publication of HRP20210739T1 publication Critical patent/HRP20210739T1/hr

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    • C07—ORGANIC CHEMISTRY
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    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
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    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70575—NGF/TNF-superfamily, e.g. CD70, CD95L, CD153, CD154
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    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70596—Molecules with a "CD"-designation not provided for elsewhere
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    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
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    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2815—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD8
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    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
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    • C07—ORGANIC CHEMISTRY
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    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/522—CH1 domain
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    • C07K2317/526—CH3 domain
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    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
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    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies

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Claims (23)

1. Molekula koja veže antigen i sadrži trimer obitelji TNF liganada, naznačena time, da sadrži (a) barem jednu Fab molekulu sposobnu za specifično vezivanje na CD19, (b) prvi i drugi polipeptid koji su međusobno povezani disulfidnom vezom, pri čemu molekulu koja veže antigen karakterizira to da (i) prvi polipeptid sadrži CH1 ili CL domenu, a drugi polipeptid sadrži CL ili CH1 domenu, pri čemu je drugi polipeptid povezan s prvim polipeptidom disulfidnom vezom između CH1 i CL domene, i pri čemu prvi polipeptid sadrži dvije ektodomene 4-1BBL-a, koje sadrže aminokiselinski slijed odabran iz skupine koja se sastoji od SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 96, SEQ ID NO: 373, SEQ ID NO: 374 i SEQ ID NO: 375, koji su međusobno povezani i povezani s CH1 ili CL domenom preko peptidnog veznika, te pri čemu drugi polipeptid sadrži jednu navedenu ektodomenu navedenog 4-1BBL-a, koja sadrži aminokiselinski slijed odabran iz skupine koja se sastoji od SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 96, SEQ ID NO: 373, SEQ ID NO: 374 i SEQ ID NO: 375, povezan preko peptidnog veznika s CL ili CH1 domenom navedenog polipeptida, ili (ii) prvi polipeptid sadrži CH3 domenu, a drugi polipeptid sadrži CH3 domenu, i pri čemu prvi polipeptid sadrži dvije ektodomene 4-1BBL-a, koje sadrže aminokiselinski slijed odabran iz skupine koja se sastoji od SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 96, SEQ ID NO: 373, SEQ ID NO: 374 i SEQ ID NO: 375, koji su međusobno povezani i povezani s C-krajem CH3 domene preko peptidnog veznika, i pri čemu drugi polipeptid sadrži samo jednu ektodomenu navedenog 4-1BBL-a, koja sadrži aminokiselinski slijed odabran iz skupine koja se sastoji od SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 96, SEQ ID NO: 373, SEQ ID NO: 374 i SEQ ID NO: 375, povezan preko peptidnog veznika na C-kraj CH3 domene navedenog polipeptida, ili (iii) prvi polipeptid sadrži VH-CL ili VL-CH1 domenu, a drugi polipeptid sadrži VL-CH1 domenu ili VH-CL domenu, pri čemu je drugi polipeptid vezan za prvi polipeptid disulfidnom vezom između CH1 i CL domene, a pri čemu prvi polipeptid sadrži dvije ektodomene 4-1BBL-a koje sadrže aminokiselinski slijed odabran iz skupine koja se sastoji od SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 96, SEQ ID NO: 373, SEQ ID NO: 374 i SEQ ID NO: 375, koji su međusobno povezani i povezani s VH ili VL preko peptidnog veznika, a pri čemu drugi polipeptid sadrži jednu ektodomenu navedenog 4-1BBL-a, koji sadrži aminokiselinski slijed odabran iz skupine koja se sastoji od SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 96, SEQ ID NO: 373, SEQ ID NO: 374 i SEQ ID NO: 375, povezan preko peptidnog veznika na VL ili VH navedenog polipeptida, i (c) Fc domenu koja se sastoji od prve i druge podjedinice sposobne za stabilno udruživanje.
2. Molekula koja veže antigen i sadrži trimer TNF ligand obitelji, prema bilo kojem od patentnih zahtjeva 1 do 2, naznačena time, da ektodomena 4-1BBL-a sadrži aminokiselinski slijed odabran između SEQ ID NO: 1 ili SEQ ID NO: 96.
3. Molekula koja veže antigen i sadrži trimer TNF ligand obitelji prema bilo kojem od patentnih zahtjeva 1 do 2, naznačena time, da ektodomena 4-1BBL-a sadrži aminokiselinski slijed SEQ ID NO: 96.
4. Molekula koja veže antigen i sadrži trimer TNF ligand obitelji prema bilo kojem od patentnih zahtjeva 1 do 3, naznačena time, da sadrži (a) barem jednu Fab molekulu sposobnu za specifično vezivanje na CD19 i (b) prvi i drugi polipeptid koji su međusobno povezani disulfidnom vezom, naznačeni time, da je molekula koja vezuje antigen karakterizirana time da prvi polipeptid sadrži aminokiselinski slijed odabran iz skupine koja se sastoji od SEQ ID NO: 5, SEQ ID NO: 97, SEQ ID NO: 98 i SEQ ID NO: 99, naznačen time, da drugi polipeptid sadrži aminokiselinski slijed odabran iz skupine koja se sastoji od SEQ ID NO: 1, SEQ ID NO: 96, SEQ ID NO: 3 i SEQ ID NO: 4.
5. Molekula koja veže antigen i sadrži trimer TNF ligand obitelji prema bilo kojem od patentnih zahtjeva 1 do 4, naznačena time, da sadrži (a) barem jednu Fab molekulu sposobnu za specifično vezivanje na CD19 i (b) prvi polipeptid koji sadrži CH1 Ili CL domenu te drugi polipeptid koji sadrži CL ili CH1 domenu, pri čemu je drugi polipeptid povezan s prvim polipeptidom disulfidnom vezom između CH1 i CL domene, i pri čemu molekulu koja veže antigen karakterizira to da prvi polipeptid sadrži dvije ektodomene 4-1BBL-a, koje sadrže aminokiselinski slijed odabran iz skupine koja se sastoji od SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 96, SEQ ID NO: 373, SEQ ID NO: 374 i SEQ ID NO: 375, koji su međusobno povezani i povezani s CH1 ili CL domenom preko peptidnog veznika, a drugi polipeptid sadrži jednu ektodomenu navedenog 4-1BBL-a, koja sadrži aminokiselinski slijed odabran iz skupine koja se sastoji od SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 96, SEQ ID NO: 373, SEQ ID NO: 374 i SEQ ID NO: 375, koji su povezani preko peptidnog veznika na CL ili CH1 domenu navedenog polipeptida.
6. Molekula koja veže antigen i sadrži trimer obitelji TNF liganada prema bilo kojem od patentnih zahtjeva 1 do 5, naznačena time, da je Fc domena IgG, osobito IgG1 Fc domena ili IgG4 Fc domena.
7. Molekula koja veže antigen i sadrži trimer obitelji TNF liganada prema bilo kojem od patentnih zahtjeva 1 do 6, naznačena time, da je Fc domena IgG1 Fc domena koja sadrži supstitucije aminokiselina na pozicijama 234 i 235 (EU numeriranje) i/ili 329 (EU numeriranje).
8. Molekula koja veže antigen i sadrži trimer TNF ligand obitelji prema bilo kojem od patentnih zahtjeva 1 do 7, naznačena time, da molekula koja veže antigen sadrži prvi teški lanac i prvi laki lanac, a oba sadrže Fab molekulu sposobnu za specifično vezivanje na CD19, prvi peptid koji sadrži dvije ektodomene 4-1BBL-a koje sadrže aminokiselinski slijed odabran iz skupine koja se sastoji od SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 96, SEQ ID NO: 373, SEQ ID NO: 374 i SEQ ID NO: 375, međusobno povezane preko prvog peptidnog veznika koji je na svom C-kraju spojen preko drugog peptidnog veznika s drugim teškim ili lakim lancem, a drugi peptid sadrži jednu ektodomenu navedenog 4-1BBL-a, koji sadrži aminokiselinski slijed odabran iz skupine koja se sastoji od SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 96, SEQ ID NO: 373, SEQ ID NO: 374 i SEQ ID NO: 375, koji je spojen na svom C-kraju, preko trećeg peptidnog veznika, s drugim lakim ili teškim lancem.
9. Molekula koja veže antigen i sadrži trimer obitelji TNF liganada prema bilo kojem od patentnih zahtjeva 1 do 8, naznačena time, da molekula koja veže antigen sadrži (a) prvi teški lanac i prvi laki lanac, a oba sadrže Fab molekulu sposobnu za specifično vezivanje na CD19, (b) drugi teški lanac koji sadrži aminokiselinski slijed odabran iz skupine koju čine SEQ ID NO: 5, SEQ ID NO: 97, SEQ ID NO: 98 i SEQ ID NO: 99, i drugi laki lanac koji sadrži aminokiselinski slijed odabran iz skupine koju čine SEQ ID NO: 1, SEQ ID NO: 96, SEQ ID NO: 3 i SEQ ID NO: 4.
10. Molekula koja veže antigen i sadrži trimer obitelji TNF liganada prema bilo kojem od patentnih zahtjeva 1 do 9, naznačena time, da Fab molekula sposobna za specifično vezivanje na CD19 sadrži VH domenu koja sadrži (i) CDR-H1 koji sadrži aminokiselinski slijed SEQ ID NO: 195 ili SEQ ID NO: 252, (ii) CDR-H2 koji sadrži aminokiselinski slijed SEQ ID NO: 196 ili SEQ ID NO: 253, i (iii) CDR-H3 koji sadrži aminokiselinski slijed SEQ ID NO: 197 ili SEQ ID NO: 254, i VL domenu koja sadrži (iv) CDR-L1 koji sadrži aminokiselinski slijed SEQ ID NO: 198 ili SEQ ID NO: 249, (v) CDR-L2 koji sadrži aminokiselinski slijed SEQ ID NO: 199 ili SEQ ID NO: 250, i (vi) CDR-L3 koji sadrži aminokiselinski slijed SEQ ID NO: 200 ili SEQ ID NO: 251.
11. Molekula koja veže antigen i sadrži trimer obitelji TNF liganada prema bilo kojem od patentnih zahtjeva 1 do 10, naznačena time, da Fab molekula sposobna za specifično vezivanje na CD19 sadrži varijabilni teški lanac koji sadrži aminokiselinski slijed SEQ ID NO: 201 i varijabilni laki lanac koji sadrži aminokiselinski slijed SEQ ID NO: 202, ili u kojoj Fab molekula sposobna za specifično vezivanje na CD19 sadrži varijabilni teški lanac koji sadrži aminokiselinski slijed SEQ ID NO: 357 i varijabilni laki lanac koji sadrži aminokiselinski slijed SEQ ID NE: 358.
12. Molekula koja veže antigen i sadrži trimer obitelji TNF liganada prema bilo kojem od patentnih zahtjeva 1 do 11, naznačena time, da molekula koja veže antigen sadrži (i) prvi teški lanac koji sadrži VH domenu koja sadrži aminokiselinski slijed SEQ ID NO: 201, i prvi laki lanac koji sadrži VL domenu koja sadrži aminokiselinski slijed SEQ ID NO: 202, ili prvi teški lanac koji sadrži VH domenu koja sadrži aminokiselinski slijed SEQ ID NO: 357, i prvi laki lanac koji sadrži VL domenu koja sadrži aminokiselinski slijed SEQ ID NO: 358, (ii) drugi teški lanac koji sadrži aminokiselinski slijed odabran iz skupine koja se sastoji od SEQ ID NO: 14, SEQ ID NO: 108, SEQ ID NO: 111 i SEQ ID NO: 113, i (iii) drugi laki lanac koji sadrži aminokiselinski slijed SEQ ID NO: 15, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 112 i SEQ ID NO: 114.
13. Molekula koja veže antigen i sadrži trimer obitelji TNF liganada prema bilo kojem od patentnih zahtjeva 1 do 11, naznačena time, da molekula koja veže antigen sadrži (i) prvi teški lanac koji sadrži VH domenu koja sadrži aminokiselinski slijed SEQ ID NO: 201, i prvi laki lanac koji sadrži VL domenu koja sadrži aminokiselinski slijed SEQ ID NO: 202, ili prvi teški lanac koji sadrži VH domenu koja sadrži aminokiselinski slijed SEQ ID NO: 357, i prvi laki lanac koji sadrži VL domenu koja sadrži aminokiselinski slijed SEQ ID NO: 358, (ii) drugi teški lanac koji sadrži aminokiselinski slijed odabran iz skupine koja se sastoji od SEQ ID NO: 115, SEQ ID NO: 117, SEQ ID NO: 119 i SEQ ID NO: 173, i (iii) drugi laki lanac koji sadrži aminokiselinski slijed odabran iz skupine koja se sastoji od SEQ ID NO: 116, SEQ ID NO: 118, SEQ ID NO: 120 i SEQ ID NO: 174.
14. Molekula koja veže antigen i sadrži trimer obitelji TNF liganada prema bilo kojem od patentnih zahtjeva 1 do 11, ili 13, naznačena time, da sadrži prvi teški lanac koji sadrži aminokiselinski slijed SEQ ID NO: 205, prvi laki lanac koji sadrži aminokiselinski slijed SEQ ID NO: 206, drugi teški lanac koji sadrži aminokiselinski slijed SEQ ID NO: 119 i drugi laki lanac koji sadrži aminokiselinski slijed SEQ ID NO: 120.
15. Molekula koja veže antigen i sadrži trimer obitelji TNF liganada prema bilo kojem od patentnih zahtjeva 1 do 11, ili 13, koja sadrži prvi teški lanac koji sadrži aminokiselinski slijed SEQ ID NO: 306, prvi laki lanac koji sadrži aminokiselinski slijed SEQ ID NO: 279, drugi teški lanac koji sadrži aminokiselinski slijed SEQ ID NO: 119 i drugi laki lanac koji sadrži aminokiselinski slijed SEQ ID NO: 120.
16. Molekula koja veže antigen i sadrži trimer obitelji TNF liganada prema bilo kojem od patentnih zahtjeva 1 do 11, naznačena time, da molekula koja veže antigen sadrži (i) Prvi teški lanac koji sadrži aminokiselinski slijed SEQ ID NO: 209, drugi teški lanac koji sadrži aminokiselinski slijed SEQ ID NO: 210, i dva laka lanca koja sadrže aminokiselinski slijed SEQ ID NO: 206, ili (ii) Prvi teški lanac koji sadrži aminokiselinski slijed SEQ ID NO: 213, drugi teški lanac koji sadrži aminokiselinski slijed SEQ ID NO: 214, i dva laka lanca koja sadrže aminokiselinski slijed SEQ ID NO: 206, ili (iii) Prvi teški lanac koji sadrži aminokiselinski slijed SEQ ID NO: 309, drugi teški lanac koji sadrži aminokiselinski slijed SEQ ID NO: 310, i dva laka lanca koja sadrže aminokiselinski slijed SEQ ID NO: 279, ili (iv) Prvi teški lanac koji sadrži aminokiselinski slijed SEQ ID NO: 313, drugi teški lanac koji sadrži aminokiselinski slijed SEQ ID NO: 314, i dva laka lanca koja sadrže aminokiselinski slijed SEQ ID NO: 279.
17. Izolirani polinukleotid, naznačen time, da kodira molekulu koja veže antigen i sadrži trimer obitelji TNF liganada prema bilo kojem od patentnih zahtjeva 1 do 16.
18. Vektor, posebice vektor za ekspresiju, naznačen time, da sadrži izolirani polinukleotid prema patentnom zahtjevu 16.
19. Stanica domaćina, naznačena time, da sadrži izolirani polinukleotid prema patentnom zahtjevu 17 ili vektor prema patentnom zahtjevu 18.
20. Postupak za proizvodnju molekule koja veže antigen i sadrži trimer obitelji TNF liganada prema bilo kojem od patentnih zahtjeva 1 do 16, naznačen time, da sadrži korake za (i) uzgoj stanice domaćina prema patentnom zahtjevu 19, pod uvjetima pogodnim za ekspresiju molekule koja veže antigen, i (ii) izdvajanje molekule koja veže antigen.
21. Farmaceutski pripravak, naznačen time, da sadrži molekulu koja veže antigen i sadrži trimer obitelji TNF liganada prema bilo kojem od patentnih zahtjeva od 1 do 16 i barem jedan farmaceutski prihvatljiv nosač.
22. Molekula koja veže antigen i sadrži trimer obitelji TNF liganada prema bilo kojem od patentnih zahtjeva od 1 do 16 ili farmaceutski pripravak prema patentnom zahtjevu 21, naznačeni time, da je za uporabu kao medikament.
23. Molekula koja veže antigen i sadrži trimer obitelji TNF liganada prema bilo kojem od patentnih zahtjeva od 1 do 16 ili farmaceutski pripravak prema patentnom zahtjevu 21, naznačeni time, da su za uporabu u liječenju raka.
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