HRP20210240T1 - Dual variable region antibody-like binding proteins having cross-over binding region orientation - Google Patents

Dual variable region antibody-like binding proteins having cross-over binding region orientation Download PDF

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HRP20210240T1
HRP20210240T1 HRP20210240TT HRP20210240T HRP20210240T1 HR P20210240 T1 HRP20210240 T1 HR P20210240T1 HR P20210240T T HRP20210240T T HR P20210240TT HR P20210240 T HRP20210240 T HR P20210240T HR P20210240 T1 HRP20210240 T1 HR P20210240T1
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variable domain
immunoglobulin
antibody
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heavy chain
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HRP20210240TT
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Nicolas Baurin
Christian Beil
Carsten Corvey
Christian Lange
Danxi Li
Vincent Mikol
Anke Steinmetz
Rao Ercole
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Sanofi
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Priority claimed from EP16205057.9A external-priority patent/EP3199547B1/en
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Publication of HRP20210240T1 publication Critical patent/HRP20210240T1/en

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Claims (16)

1. Vezujući protein sličan protutijelu koji sadrži četiri polipeptidna lanca koji tvore četiri mjesta za vezanje antigena koja su sposobna specifično vezati jedan ili više antigenskih ciljeva, naznačen time što dva polipeptidna lanca imaju strukturu predstavljenu formulom: VL1-L1-VL2-L2-CL[I] i dva polipeptidna lanca imaju strukturu predstavljenu formulom: VH2-L3-VH1-L4-CH1-Fc [II] pri čemu: VL1 je prva varijabilna domena lakog lanca imunoglobulina; VL2 je druga varijabilna domena lakog lanca imunoglobulina; VH1 je prva varijabilna domena teškog lanca imunoglobulina; VH2 je druga varijabilna domena teškog lanca imunoglobulina; CL je konstantna domena lakog lanca imunoglobulina; CH1 je konstantna domena teškog lanca imunoglobulina CH1; Fc je zglobna regija imunoglobulina i CH2, CH3 konstantne domene teškog lanca imunoglobulina; i L1, L2, L3, i L4 su aminokiselinske poveznice; pri čemu duljina od L4 je najmanje dvostruka duljina od L2; i duljina od L3 je najmanje dvostruka duljina od L1; i pri čemu poveznice osiguravaju dovoljnu pokretljivost za uparivanje VL1 i VH1, i za uparivanje VL2 i VH2, i polipeptidi s formulom I i polipeptidi s formulom II tvore unakrsni par laki lanac-teški lanac.1. An antibody-like binding protein containing four polypeptide chains that form four antigen-binding sites capable of specifically binding one or more antigenic targets, characterized in that the two polypeptide chains have the structure represented by the formula: VL1-L1-VL2-L2-CL[I] and two polypeptide chains have a structure represented by the formula: VH2-L3-VH1-L4-CH1-Fc [II] whereby: VL1 is the first variable domain of the immunoglobulin light chain; VL2 is the second variable domain of the immunoglobulin light chain; VH1 is the first variable domain of the immunoglobulin heavy chain; VH2 is the second variable domain of the immunoglobulin heavy chain; CL is the immunoglobulin light chain constant domain; CH1 is the constant domain of the heavy chain of immunoglobulin CH1; Fc is the immunoglobulin hinge region and the CH2, CH3 constant domain of the immunoglobulin heavy chain; and L1, L2, L3, and L4 are amino acid linkages; whereby the length of L4 is at least twice the length of L2; and the length of L3 is at least twice the length of L1; and wherein the linkers provide sufficient mobility for the pairing of VL1 and VH1, and for the pairing of VL2 and VH2, and both the polypeptides of formula I and the polypeptides of formula II form a light chain-heavy chain cross-pair. 2. Vezujući protein sličan protutijelu koji sadrži dva polipeptidna lanca koji tvore dva mjesta za vezanje antigena koja su sposobna specifično vezati jedan ili više antigenskih ciljeva, naznačen time što prvi polipeptidni lanac ima strukturu predstavljenu formulom: VL1-L1-VL2-L2-CL[I] i drugi polipeptidni lanac ima strukturu predstavljenu formulom: VH2-L3-VH1-L4-CH1[II] pri čemu: VL1 je prva varijabilna domena lakog lanca imunoglobulina; VL2 je druga varijabilna domena lakog lanca imunoglobulina; VH1 je prva varijabilna domena teškog lanca imunoglobulina; VH2 je druga varijabilna domena teškog lanca imunoglobulina; CL je konstantna domena lakog lanca imunoglobulina; CH1 je konstantna domena teškog lanca imunoglobulina CH1; i L1, L2, L3, i L4 su aminokiselinske poveznice; pri čemu duljina od L4 je najmanje dvostruka duljina od L2; i duljina od L3 je najmanje dvostruka duljina od L1; i pri čemu poveznice osiguravaju dovoljnu pokretljivost za uparivanje VL1 i VH1, i za uparivanje VL2 i VH2, i prvi i drugi polipeptidi tvore unakrsni par laki lanac-teški lanac.2. An antibody-like binding protein containing two polypeptide chains that form two antigen-binding sites capable of specifically binding one or more antigenic targets, characterized in that the first polypeptide chain has a structure represented by the formula: VL1-L1-VL2-L2-CL[I] and the second polypeptide chain has a structure represented by the formula: VH2-L3-VH1-L4-CH1[II] whereby: VL1 is the first variable domain of the immunoglobulin light chain; VL2 is the second variable domain of the immunoglobulin light chain; VH1 is the first variable domain of the immunoglobulin heavy chain; VH2 is the second variable domain of the immunoglobulin heavy chain; CL is the immunoglobulin light chain constant domain; CH1 is the constant domain of the heavy chain of immunoglobulin CH1; and L1, L2, L3, and L4 are amino acid linkages; whereby the length of L4 is at least twice the length of L2; and the length of L3 is at least twice the length of L1; and wherein the linkers provide sufficient mobility for the pairing of VL1 and VH1, and for the pairing of VL2 and VH2, and both the first and second polypeptides form a light chain-heavy chain cross-pair. 3. Vezujući protein sličan protutijelu prema bilo kojem od patentnih zahtjeva 1-2, naznačen time što je jedan ili više antigenskih ciljeva odabran iz skupine koja se sastoji od B7.1, B7.2, BAFF, BlyS, C3, C5, CCL11 (eotaksin), CCL15 (MIP-1d), CCL17 (TARC), CCL19 (MIP-3b), CCL2 (MCP-1), CCL20 (MIP-3a), CCL21 (MIP-2), SLC, CCL24 (MPIF-2/eotaxin-2), CCL25 (TECK), CCL26 (eotaxin-3), CCL3 (MIP-1a), CCL4 (MIP-1b), CCL5 (RANTES), CCL7 (MCP-3), CCL8 (mcp-2), CD3, CD19, CD20, CD24, CD40, CD40L, CD80, CD86, CDH1 (E-kadherin), Hitinaze, CSF1 (M-CSF), CSF2 (GM-CSF), CSF3 (GCSF), CTLA4, CX3CL1 (SCYD1), CXCL12 (SDF1), CXCL13, EGFR, FCER1A, FCER2, HER2, IGF1R, IL-1, IL-12, IL13, IL15, IL17, IL18, ILIA, IL1B, IL1F10, IL1β, IL2, IL4, IL6, IL7, IL8, IL9, IL12/23, IL22, IL23, IL25, IL27, IL35, ITGB4 (b 4 integrin), LEP (leptin), MHC razred II, TLR2, TLR4, TLR5, TNF, TNFα, TNFSF4 (OX40 ligand), TNFSF5 (CD40 ligand), Toll-like receptori, TREM1, TSLP, TWEAK, XCR1 (GPR5/CCXCR1), DNGR-1(CLEC91), i HMGB1.3. An antibody-like binding protein according to any one of claims 1-2, characterized in that one or more antigenic targets are selected from the group consisting of B7.1, B7.2, BAFF, BlyS, C3, C5, CCL11 ( eotaxin), CCL15 (MIP-1d), CCL17 (TARC), CCL19 (MIP-3b), CCL2 (MCP-1), CCL20 (MIP-3a), CCL21 (MIP-2), SLC, CCL24 (MPIF-2 /eotaxin-2), CCL25 (TECK), CCL26 (eotaxin-3), CCL3 (MIP-1a), CCL4 (MIP-1b), CCL5 (RANTES), CCL7 (MCP-3), CCL8 (mcp-2) , CD3, CD19, CD20, CD24, CD40, CD40L, CD80, CD86, CDH1 (E-cadherin), Chitinases, CSF1 (M-CSF), CSF2 (GM-CSF), CSF3 (GCSF), CTLA4, CX3CL1 (SCYD1 ), CXCL12 (SDF1), CXCL13, EGFR, FCER1A, FCER2, HER2, IGF1R, IL-1, IL-12, IL13, IL15, IL17, IL18, ILIA, IL1B, IL1F10, IL1β, IL2, IL4, IL6, IL7 , IL8, IL9, IL12/23, IL22, IL23, IL25, IL27, IL35, ITGB4 (b 4 integrin), LEP (leptin), MHC class II, TLR2, TLR4, TLR5, TNF, TNFα, TNFSF4 (OX40 ligand) , TNFSF5 (CD40 ligand), Toll-like receptors, TREM1, TSLP, TWEAK, XCR1 (GPR5/CCXCR1), DNGR-1(CLEC91), and HMGB1. 4. Vezujući protein sličan protutijelu prema bilo kojem od patentnih zahtjeva 1-3, naznačen time što je vezujući protein bispecifičan i sposoban vezati dva različita antigenska cilja, po mogućnosti IL-4 i IL-13.4. An antibody-like binding protein according to any one of claims 1-3, characterized in that the binding protein is bispecific and capable of binding two different antigenic targets, preferably IL-4 and IL-13. 5. Vezujući protein sličan protutijelu prema bilo kojem od patentnih zahtjeva 1-4, naznačen time što su dva različita antigenska cilja odabrana iz skupine koja sadrži IL4 i IL13, IGF1R i HER2, IGF1R i EGFR, EGFR i HER2, BK i IL13, PDL-1 i CTLA-4, CTLA4 i MHC razred II, IL-12 i IL-18, IL-1α i IL-1β, TNFα i IL12/23, TNFα i IL-12p40, TNFα i IL1β, TNFα i IL-23, i IL17 i IL23.5. An antibody-like binding protein according to any one of claims 1-4, characterized in that the two different antigenic targets are selected from the group consisting of IL4 and IL13, IGF1R and HER2, IGF1R and EGFR, EGFR and HER2, BK and IL13, PDL -1 and CTLA-4, CTLA4 and MHC class II, IL-12 and IL-18, IL-1α and IL-1β, TNFα and IL12/23, TNFα and IL-12p40, TNFα and IL1β, TNFα and IL-23 , and IL17 and IL23. 6. Vezujući protein sličan protutijelu prema bilo kojem od patentnih zahtjeva 1-5, naznačen time što je vezujući protein sposoban inhibirati funkciju jednog ili više antigenskih ciljeva.6. An antibody-like binding protein according to any one of claims 1-5, characterized in that the binding protein is capable of inhibiting the function of one or more antigenic targets. 7. Vezujući protein sličan protutijelu prema bilo kojem od patentnih zahtjeva 1-6, naznačen time što najmanje jedna od poveznica odabrana iz skupine koja se sastoji od L1, L2, L3, i L4 sadrži najmanje jedan cisteinski ostatak.7. An antibody-like binding protein according to any one of claims 1-6, characterized in that at least one of the linkers selected from the group consisting of L1, L2, L3, and L4 contains at least one cysteine residue. 8. Izolirana molekula nukleinske kiseline naznačena time što sadrži nukleotidnu sekvencu koja kodira vezujući protein sličan protutijelu prema bilo kojem od patentnih zahtjeva 1-7.8. An isolated nucleic acid molecule characterized in that it contains a nucleotide sequence encoding an antibody-like binding protein according to any one of claims 1-7. 9. Ekspresijski vektor naznačen time što sadrži molekulu nukleinske kiseline prema zahtjevu 8.9. An expression vector characterized by the fact that it contains a nucleic acid molecule according to claim 8. 10. Izolirana stanica domaćina koja sadrži sadrži molekulu nukleinske kiseline prema zahtjevu 8 ili ekspresijski vektor prema zahtjevu 9, naznačena time što je stanica domaćina poželjno stanica sisavca ili stanica insekta.10. An isolated host cell containing a nucleic acid molecule according to claim 8 or an expression vector according to claim 9, characterized in that the host cell is preferably a mammalian cell or an insect cell. 11. Farmaceutski pripravak naznačen time što sadrži farmaceutski prihvatljiv nosač i terapeutski učinkovitu količinu vezujućeg proteina sličnog protutijelu prema bilo kojem od patentnih zahtjeva 1-7.11. A pharmaceutical preparation characterized in that it contains a pharmaceutically acceptable carrier and a therapeutically effective amount of an antibody-like binding protein according to any one of claims 1-7. 12. Postupak za proizvodnju vezujućeg proteina sličnog protutijelu prema bilo kojem od patentnih zahtjeva 1, i 3 do 7, naznačen time što obuhvaća ekspresiju u stanici jedne ili više molekula nukleinske kiseline koje kodiraju polipeptide koji imaju strukture predstavljene formulama [I] i [II] ispod: VL1-L1-VL2-L2-CL[I] VH2-L3-VH1-L4-CH1-Fc [II] pri čemu: VL1 je prva varijabilna domena lakog lanca imunoglobulina; VL2 je druga varijabilna domena lakog lanca imunoglobulina; VH1 je prva varijabilna domena teškog lanca imunoglobulina; VH2 je druga varijabilna domena teškog lanca imunoglobulina; CL je konstantna domena lakog lanca imunoglobulina; CH1 je konstantna domena teškog lanca imunoglobulina CH1; Fc je zglobna regija imunoglobulina i CH2, CH3 konstantne domene teškog lanca imunoglobulina; i L1, L2, L3, i L4 su aminokiselinske poveznice; pri čemu duljina od L4 je najmanje dvostruka duljina od L2; i pri čemu duljina od L3 je najmanje dvostruka duljina od L1; i pri čemu poveznice osiguravaju dovoljnu pokretljivost za uparivanje VL1 i VH1, i za uparivanje VL2 i VH2, i polipeptidi s formulom I i polipeptidi s formulom II tvore unakrsni par laki lanac-teški lanac.12. A method for the production of a binding protein similar to an antibody according to any of claims 1, and 3 to 7, characterized in that it comprises the expression in a cell of one or more nucleic acid molecules encoding polypeptides having the structures represented by formulas [I] and [II] under: VL1-L1-VL2-L2-CL[I] VH2-L3-VH1-L4-CH1-Fc [II] whereby: VL1 is the first variable domain of the immunoglobulin light chain; VL2 is the second variable domain of the immunoglobulin light chain; VH1 is the first variable domain of the immunoglobulin heavy chain; VH2 is the second variable domain of the immunoglobulin heavy chain; CL is the immunoglobulin light chain constant domain; CH1 is the constant domain of the heavy chain of immunoglobulin CH1; Fc is the immunoglobulin hinge region and the CH2, CH3 constant domain of the immunoglobulin heavy chain; and L1, L2, L3, and L4 are amino acid linkages; wherein the length of L4 is at least twice the length of L2; and wherein the length of L3 is at least twice the length of L1; and wherein the linkers provide sufficient mobility for the pairing of VL1 and VH1, and for the pairing of VL2 and VH2, and both the polypeptides of formula I and the polypeptides of formula II form a light chain-heavy chain cross-pair. 13. Postupak za proizvodnju vezujućeg proteina sličnog protutijelu prema bilo kojem od patentnih zahtjeva 2 do 7, naznačen time što obuhvaća ekspresiju u stanici jedne ili više molekula nukleinske kiseline koje kodiraju polipeptide koji imaju strukture predstavljene formulama [I] i [II] ispod: VL1-L1-VL2-L2-CL[I] VH2-L3-VH1-L4-CH1[II] pri čemu: VL1 je prva varijabilna domena lakog lanca imunoglobulina; VL2 je druga varijabilna domena lakog lanca imunoglobulina; VH1 je prva varijabilna domena teškog lanca imunoglobulina; VH2 je druga varijabilna domena teškog lanca imunoglobulina; CL je konstantna domena lakog lanca imunoglobulina; CH1 je konstantna domena teškog lanca imunoglobulina CH1; i L1, L2, L3, i L4 su aminokiselinske poveznice; pri čemu duljina od L4 je najmanje dvostruka duljina od L2; i pri čemu duljina od L3 je najmanje dvostruka duljina od L1; i pri čemu poveznice osiguravaju dovoljnu pokretljivost za uparivanje VL1 i VH1, i za uparivanje VL2 i VH2, i polipeptid s formulom I i polipeptid s formulom II tvore unakrsni par laki lanac-teški lanac.13. A method for the production of an antibody-like binding protein according to any one of claims 2 to 7, characterized in that it comprises the expression in a cell of one or more nucleic acid molecules encoding polypeptides having the structures represented by formulas [I] and [II] below: VL1-L1-VL2-L2-CL[I] VH2-L3-VH1-L4-CH1[II] whereby: VL1 is the first variable domain of the immunoglobulin light chain; VL2 is the second variable domain of the immunoglobulin light chain; VH1 is the first variable domain of the immunoglobulin heavy chain; VH2 is the second variable domain of the immunoglobulin heavy chain; CL is the immunoglobulin light chain constant domain; CH1 is the constant domain of the heavy chain of immunoglobulin CH1; and L1, L2, L3, and L4 are amino acid linkages; wherein the length of L4 is at least twice the length of L2; and wherein the length of L3 is at least twice the length of L1; and wherein the linkers provide sufficient mobility for the pairing of VL1 and VH1, and for the pairing of VL2 and VH2, and both the polypeptide of formula I and the polypeptide of formula II form a light chain-heavy chain cross-pair. 14. Postupak za proizvodnju vezujućeg proteina sličnog protutijelu koji sadrži četiri polipeptidna lanca koji tvore četiri mjesta za vezanje antigena, naznačen time što obuhvaća: (a) identificiranje varijabilne domene prvog protutijela koja veže prvi ciljni antigen i varijabilne domene drugog protutijela koje veže drugi ciljni antigen, od kojih svaka sadrži VL, i VH; (b) dodjeljivanje lakog lanca kao lanca predloška; (c) dodjeljivanje VL varijabilne domene prvog protutijela i varijabilne domene drugog protutijela kaoVL1; (d) dodjeljivanje VL2, VH1, i VH2 prema formulama [I] i [II] ispod: VL1-L1-VL2-L2-CL[I] VH1-L3-VH1-L4-CH1-Fc [II] (e) određivanje maksimalne i minimalne duljine za L1, L2, L3, i L4; (f) generiranje polipeptidnih struktura s formulama I i II; (g) odabir polipeptidnih struktura s formulama I i II koje vežu prvi ciljni antigen i drugi ciljni antigen kada se kombiniraju da tvore vezujući protein sličan protutijelu; pri čemu: VL1 je prva varijabilna domena lakog lanca imunoglobulina; VL2 je druga varijabilna domena lakog lanca imunoglobulina; VH1 je prva varijabilna domena teškog lanca imunoglobulina; VH2 je druga varijabilna domena teškog lanca imunoglobulina; CL je konstantna domena lakog lanca imunoglobulina; CH1 je konstantna domena teškog lanca imunoglobulina CH1; Fc je zglobna regija imunoglobulina i CH2, CH3 konstantne domene teškog lanca imunoglobulina; i L1, L2, L3, i L4 su aminokiselinske poveznice; pri čemu duljina od L4 je najmanje dvostruka duljina od L2; i pri čemu duljina od L3 je najmanje dvostruka duljina od L1; i pri čemu poveznice osiguravaju dovoljnu pokretljivost za uparivanje VL1 i VH1, i za uparivanje VL2 i VH2, i polipeptidi s formulom I i polipeptidi s formulom II tvore unakrsni par laki lanac-teški lanac.14. A method for the production of a binding protein similar to an antibody containing four polypeptide chains that form four antigen binding sites, characterized in that it comprises: (a) identifying a variable domain of the first antibody that binds the first target antigen and a variable domain of the second antibody that binds the second target antigen, each comprising a VL, and a VH; (b) assigning the light chain as the template chain; (c) assigning the VL variable domain of the first antibody and the variable domain of the second antibody as VL1; (d) assigning VL2, VH1, and VH2 according to formulas [I] and [II] below: VL1-L1-VL2-L2-CL[I] VH1-L3-VH1-L4-CH1-Fc [II] (e) determining the maximum and minimum length for L1, L2, L3, and L4; (f) generating polypeptide structures of formulas I and II; (g) selecting polypeptide structures of formulas I and II that bind the first target antigen and the second target antigen when combined to form an antibody-like binding protein; whereby: VL1 is the first variable domain of the immunoglobulin light chain; VL2 is the second variable domain of the immunoglobulin light chain; VH1 is the first variable domain of the immunoglobulin heavy chain; VH2 is the second variable domain of the immunoglobulin heavy chain; CL is the immunoglobulin light chain constant domain; CH1 is the constant domain of the heavy chain of immunoglobulin CH1; Fc is the immunoglobulin hinge region and the CH2, CH3 constant domain of the immunoglobulin heavy chain; and L1, L2, L3, and L4 are amino acid linkages; wherein the length of L4 is at least twice the length of L2; and wherein the length of L3 is at least twice the length of L1; and wherein the linkers provide sufficient mobility for the pairing of VL1 and VH1, and for the pairing of VL2 and VH2, and both the polypeptides of formula I and the polypeptides of formula II form a light chain-heavy chain cross-pair. 15. Postupak za proizvodnju vezujućeg proteina sličnog protutijelu koji sadrži četiri polipeptidna lanca koji tvore četiri mjesta za vezanje antigena, naznačen time što obuhvaća: (a) identificiranje varijabilne domene prvog protutijela koja veže prvi ciljni antigen i varijabilne domene drugog protutijela koje veže drugi ciljni antigen, od kojih svaka sadrži VL, i VH; (b) dodjeljivanje lakog lanca kao lanca predloška; (c) dodjeljivanje VL varijabilne domene prvog protutijela i varijabilne domene drugog protutijela kaoVL1; (d) dodjeljivanje VL2, VH1, i VH2 prema formulama [I] i [II] ispod: VL1-L1-VL2-L2-CL[I] VH1-L3-VH1-L4-CH1[II] (e) određivanje maksimalne i minimalne duljine za L1, L2, L3, i L4; (f) generiranje polipeptidnih struktura s formulama I i II; (g) odabir polipeptidnih struktura s formulama I i II koje vežu prvi ciljni antigen i drugi ciljni antigen kada se kombiniraju da tvore vezujući protein sličan protutijelu; pri čemu: VL1 je prva varijabilna domena lakog lanca imunoglobulina; VL2 je druga varijabilna domena lakog lanca imunoglobulina; VH1 je prva varijabilna domena teškog lanca imunoglobulina; VH2 je druga varijabilna domena teškog lanca imunoglobulina; CL je konstantna domena lakog lanca imunoglobulina; CH1 je konstantna domena teškog lanca imunoglobulina CH1; i L1, L2, L3, i L4 su aminokiselinske poveznice; pri čemu duljina od L4 je najmanje dvostruka duljina od L2; i pri čemu duljina od L3 je najmanje dvostruka duljina od L1; i pri čemu poveznice osiguravaju dovoljnu pokretljivost za uparivanje VL1 i VH1, i za uparivanje VL2 i VH2, i polipeptidi s formulom I i polipeptidi s formulom II tvore unakrsni par laki lanac-teški lanac.15. A method for the production of a binding protein similar to an antibody containing four polypeptide chains that form four antigen binding sites, characterized in that it comprises: (a) identifying a variable domain of the first antibody that binds the first target antigen and a variable domain of the second antibody that binds the second target antigen, each comprising a VL, and a VH; (b) assigning the light chain as the template chain; (c) assigning the VL variable domain of the first antibody and the variable domain of the second antibody as VL1; (d) assigning VL2, VH1, and VH2 according to formulas [I] and [II] below: VL1-L1-VL2-L2-CL[I] VH1-L3-VH1-L4-CH1[II] (e) determining the maximum and minimum length for L1, L2, L3, and L4; (f) generating polypeptide structures of formulas I and II; (g) selecting polypeptide structures of formulas I and II that bind the first target antigen and the second target antigen when combined to form an antibody-like binding protein; whereby: VL1 is the first variable domain of the immunoglobulin light chain; VL2 is the second variable domain of the immunoglobulin light chain; VH1 is the first variable domain of the immunoglobulin heavy chain; VH2 is the second variable domain of the immunoglobulin heavy chain; CL is the immunoglobulin light chain constant domain; CH1 is the constant domain of the heavy chain of immunoglobulin CH1; and L1, L2, L3, and L4 are amino acid linkages; wherein the length of L4 is at least twice the length of L2; and wherein the length of L3 is at least twice the length of L1; and wherein the linkers provide sufficient mobility for the pairing of VL1 and VH1, and for the pairing of VL2 and VH2, and both the polypeptides of formula I and the polypeptides of formula II form a light chain-heavy chain cross-pair. 16. Postupak prema patentnom zahtjevu 14 ili 15, naznačen time što su prva varijabilna domena protutijela i druga varijabilna domena protutijela, iste.16. The method according to patent claim 14 or 15, characterized in that the first variable domain of the antibody and the second variable domain of the antibody are the same.
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