Engineered bispecific molecules and methods of use

Abstract

Provided herein are bispecific molecules and methods of treating using the bispecific molecules, wherein the bispecific molecules comprise a first binding domain and a second binding domain, wherein the first binding domain binds TL1A, a variant thereof or a functional fragment thereof, and wherein the second binding domain binds any one of IL-6R, IL-6, IL-12, IL-23, an IL-17 family cytokine, IL-17R, a variant thereof, and a functional fragment thereof.

Description

ENGINEERED BISPECIFIC MOLECULES AND METHODS OF USEFIELD

[0001] The disclosure generally relates to bispecific molecules is capable of binding to TL1A, and a protein selected from IL-6, IL-23, IL- 12, IL-6R, an IL- 17 family cytokine, and IL-17R.CROSS-REFERENCED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 602,120, filed on November 22, 2023, U.S. Provisional Application No. 63 / 551,580, filed on February 9, 2024, U.S. Provisional Application No. 63 / 677,245, filed on July 30, 2024, and U.S. Provisional Application No. 63 / 696,844, filed on September 19, 2024, the entire contents of each of which are incorporated herein by reference.INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing, which has been submitted via Patent Center. The Sequence Listing titled 220710-703601_PCT_SL.xml, which was created on November 22, 2024, and is 673,981 bytes in size, is hereby incorporated by reference in its entirety.BACKGROUND OF THE DISCLOSURE

[0002] Bispecific antibodies (BsAbs) are antibodies with two binding sites each independently directed at two different targets, or alternatively, two different epitopes on the same target. The therapeutic utility of BsAbs has shown to result in the potential for enhanced activity in comparison to that of mono- specific antibodies. BsAbs are understood to have broader applications for immunotherapy in treatment of various diseases.SUMMARY OF THE DISCLOSURE

[0003] Provided herein are IgG antibody constructs comprising: a TL1A binding region that binds an epitope on TL1A, a variant thereof or a functional fragment thereof, and an IL-23 binding region that binds an epitope on IL-23, a variant thereof or a functional fragment thereof, wherein said TL1A binding region comprises a TL1A binding heavy chain variable domain and a TL1A binding light chain variable domain, wherein at least one amino acid modification in said TL1A binding heavy chain variable domain and / or said TL1A binding light chain variable domain, and wherein said amino acid modification changes an isoelectric point (pl) of said IgG antibody construct relative to a pl of a corresponding IgG antibody construct prior to said amino acid modification, thereby resulting in pH- dependent binding activity for said TL1A in said IgG antibody construct, as measured by surface plasmon resonance spectroscopy. In some embodiments, said IL-23 binding region comprises an IL-23 binding heavy chain variable domain and an IL-23 binding light chain variable domain, and at least oneamino acid modification in said IL-23 binding heavy chain variable domain and / or said IL-23 binding light chain variable domain, wherein said amino acid modification changes an isoelectric point (pl) of said IgG antibody construct relative to a pl of a corresponding IgG antibody construct prior to said amino acid modification, thereby resulting in pH-dependent binding activity for said IL-23 in said IgG antibody construct, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said TL1A binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-H3 of said TL1A binding heavy chain variable domain. In some embodiments, said at least one amino acid modification comprises a substitution of at least one uncharged amino acid with a charged amino acid. In some embodiments, said at least one amino acid modification is within at least one framework region of said TL1A binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-L1, a CDR- L2, and / or a CDR-L3 of said TL1A binding light chain variable domain. In some embodiments, said at least one amino acid modification is within at least one framework region of said TL1A binding light chain variable domain. In some embodiments, said at least one amino acid modification increases binding affinity of said TL1A binding region for said TL1A in neutral pH condition by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification reduces a binding affinity of said TL1A binding region for said TL1A in acidic pH condition by at least 10% relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said IL-23 binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within at least one framework region of said IL-23 binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-L1, a CDR-L2, and / or a CDR-L3 of said IL-23 binding light chain variable domain. In some embodiments, said at least one amino acid modification is within at least one framework region of said TL1A binding light chain variable domain. In some embodiments, said at least one amino acid modification increases binding affinity of said IL-23 binding region for said IL-23 in neutral pH condition by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to said binding affinity of corresponding IL-23 binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification reduces a binding affinity of said TL1A binding region for said TL1A in acidic pH condition by at least 10% relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said IL-23 binding heavy chain variable region further binds an epitope that is present on IL-12p40, a variant thereof or a functional fragment thereof. In some embodiments, said IgG antibody construct has higher binding affinity for trimeric TL1A relative to monomeric TL1A under neutral pH condition. In some embodiments, said IgG antibody construct has higher binding affinity for monomeric TL1A relative to trimeric TL1A under neutral pH condition. In some embodiments, said IgG antibody construct has higher binding affinity for monomeric IL-23 relative to heterodimeric IL-23 under neutral pH condition. In some embodiments, said IgG antibody construct has higher binding affinity for heterodimeric IL-23 relative to monomeric IL-23 under neutral pH condition. In some embodiments, said TL1A binding light chain variable domain and said IL-23 binding light chain variable domain are at least 90%, at least 95%, at least 98% or 100% identical relative to each other. In some embodiments, said at least one amino acid modification in said TL1A binding heavy chain variable domain increases half-life of said IgG antibody construct in vivo by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to half-life of corresponding IgG antibody construct prior to said at least one amino acid modification. In some embodiments, the IgG antibody construct is an antibody, a Fab2 antibody, a bis-scFv antibody, a diabody, a DVD-Ig, a TandAb, a tandem scFv-Fc, a one-armed tandem scFv-Fc, a DART, a DART-Fc, or a functional fragment thereof. In some embodiments, the IgG antibody construct is an antibody, a variant thereof, or a functional fragment thereof. In some embodiments, the IgG antibody constructs further comprise a constant region, wherein said constant region comprises a first Fc domain and / or a second Fc domain. In some embodiments, said first Fc domain and said second Fc domain are derived from IgGl, IgG2, IgG3 or IgG4. In some embodiments, said first Fc domain and said second Fc domain are derived from IgGl constant domain. In some embodiments, said first Fc domain and said second Fc domain independently comprise M252Y, S254T, and T256E substitutions. In some embodiments, said first Fc domain and said second Fc domain independently comprise L234A and L235A substitutions. In some embodiments, said first Fc domain and said second Fc domain independently comprise P329G substitution. In some embodiments, said first Fc domain comprises a knob modification and said second Fc domain comprises a hole modification, wherein: said knob modification comprises replacing an original amino acid residue from an interface of the Fc region with an amino acid residue selected from tyrosine and tryptophan, and wherein said hole modification comprises replacing an original amino acid residue from the interface of the Fc region with an amino acid residue selected from serine, threonine, valine and alanine. In some embodiments, the first Fc domain comprises at least two modifications at positions selected from L351, F405 and Y407, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, K392 and T394, per EU numbering. In some embodiments, the first Fc domain comprises at least two modifications at positions selected from Q347, Y349, T350, K370, G371, D399 and S400, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T350, S354, E357, K360, Q362E, S364, N390, K409 and T411, per EU numbering. In some embodiments, the first Fc domain comprises at least onesubstitution at positions selected from S354 and T366, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, L368 and Y407, per EU numbering. In some embodiments, the first Fc domain comprises at least one substitution selected from S354 and T366W, per EU numbering, and the second Fc domain comprises at least one substitution selected from T366S. L368A, Y407T, and Y407V, per EU numbering. In some embodiments, said constant region comprises at least one amino acid modifications, wherein said at least one amino acid modification increases binding affinity of said constant region for a neonatal fragment crystallizable receptor (FcRn) in acidic pH condition relative to said binding affinity of corresponding constant region prior to the at least one amino acid modification, and wherein a binding affinity of said constant region for said FcRn in neutral pH condition remains within 20% of corresponding binding affinity of said corresponding constant region prior to the at least one modification. In some embodiments, said binding affinity of said constant region for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in acidic pH condition relative to the corresponding constant region prior to the at least one modification. In some embodiments, said at least one modification decreases plasma clearance (CL), increases plasma retention time, or increases plasma half-life (t'A) relative to a corresponding IgG antibody construct prior to said at least one modification in said constant region. In some embodiments, a binding affinity of said constant region for a FcRn is increased in neutral pH condition relative to said binding affinity of a corresponding constant region prior to said at least one modification, and wherein a binding affinity of said constant region for said FcRn in acidic pH condition remains within 20% of said binding affinity of corresponding constant region prior to said at least one modification. In some embodiments, said binding affinity of said constant region for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in neutral pH condition relative to said binding affinity of corresponding constant region prior to the at least one modification. In some embodiments, the at least one modification increases plasma clearance of TL1A by the IgG antibody construct, compared to a corresponding plasma clearance by an IgG antibody construct prior to the at least one modification in the constant region.

[0004] Also provided herein are IgG antibody constructs comprising a TL1A binding region that binds an epitope on TL1A, a variant thereof or a functional fragment thereof, and an IL-23 binding region that binds an epitope on IL-23, a variant thereof or a functional fragment thereof, wherein said TL1A binding region comprises a TL1A binding heavy chain variable domain, wherein said IL-23 binding region comprises an IL-23 binding heavy chain variable domain, and wherein a binding affinity of said TL1A binding region for said TL1A is at least 10% higher at pH 7.4 relative to said binding affinity at pH 5.8, as measured by surface plasmon resonance spectroscopy. In some embodiments, a binding affinity of said IL-23 binding region for said IL-23 is at least 10% higher at pH 7.4 relative to said binding affinity at pH 5.8, as measured by surface plasmon resonance spectroscopy. In some embodiments, said IgG antibody construct comprises a TL1A binding light chain variable domain thatinteract with said TL1A binding heavy chain variable domain, thereby forming said TL1A binding region, said TL1A binding heavy chain variable domain and / or said TL1A binding light chain variable domain comprises at least one amino acid modification that (a) increases binding affinity of said TL1A binding region for said TL1A relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification under neutral pH condition, as measured by surface plasmon resonance spectroscopy, and / or (b) decreases binding affinity of said TL1A binding region for said TL1A relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification under acidic pH condition, as measured by surface plasmon resonance spectroscopy. In some embodiments, said IgG antibody construct comprises an IL-23 binding light chain variable domain that interact with said IL-23 binding heavy chain variable domain, thereby forming said IL-23 binding region, said IL-23 binding heavy chain variable domain and / or said IL-23 binding light chain variable domain comprises at least one amino acid modification that (a) increases binding affinity of said IL-23 binding region for said IL-23 relative to said binding affinity of corresponding IL-23 binding region prior to said at least one amino acid modification under neutral pH condition, as measured by surface plasmon resonance spectroscopy, and / or (b) decreases binding affinity of said IL-23 binding region for said IL-23 relative to said binding affinity of corresponding IL-23 binding region prior to said at least one amino acid modification under acidic pH condition, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said TL1A binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-H3 of said TL1A binding heavy chain variable domain. In some embodiments, said at least one amino acid modification comprises a substitution of at least one uncharged amino acid with a charged amino acid. In some embodiments, said at least one amino acid modification is within at least one framework region of said TL1A binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-L1, a CDR-L2, and / or a CDR-L3 of said TL1A binding light chain variable domain. In some embodiments, said at least one amino acid modification is within at least one framework region of said TL1A binding light chain variable domain. In some embodiments, said at least one amino acid modification increases binding affinity of said TL1A binding region for said TL1A in neutral pH condition by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to said binding affinity of corresponding TL1 A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification reduces a binding affinity of said TL1A binding region for said TL1A in acidic pH condition by at least 10% relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said IL-23 binding heavy chain variable domain. In some embodiments, said at least one amino acid modificationis within at least one framework region of said IL-23 binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-L1, a CDR-L2, and / or a CDR- L3 of said IL-23 binding light chain variable domain. In some embodiments, said at least one amino acid modification is within at least one framework region of said TL1A binding light chain variable domain. In some embodiments, said at least one amino acid modification increases binding affinity of said IL-23 binding region for said IL-23 in neutral pH condition by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to said binding affinity of corresponding IL-23 binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification reduces a binding affinity of said TL1A binding region for said TL1A in acidic pH condition by at least 10% relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said IL-23 binding heavy chain variable region further binds an epitope that is present on IL- 12p40, a variant thereof or a functional fragment thereof. In some embodiments, said IgG antibody construct has higher binding affinity for trimeric TL1A relative to monomeric TL1A under neutral pH condition. In some embodiments, said IgG antibody construct has higher binding affinity for monomeric TL1A relative to trimeric TL1A under neutral pH condition. In some embodiments, said IgG antibody construct has higher binding affinity for monomeric IL-23 relative to heterodimeric IL- 23 under neutral pH condition. In some embodiments, said IgG antibody construct has higher binding affinity for heterodimeric IL-23 relative to monomeric IL-23 under neutral pH condition. In some embodiments, said TL1A binding light chain variable domain and said IL-23 binding light chain variable domain are at least 90%, at least 95%, at least 98% or 100% identical relative to each other. In some embodiments, said at least one amino acid modification in said TL1A binding heavy chain variable domain increases half-life of said IgG antibody construct in vivo by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to halflife of corresponding IgG antibody construct prior to said at least one amino acid modification. In some embodiments, the IgG antibody construct is an antibody, a Fab2 antibody, a bis-scFv antibody, a diabody, a DVD-Ig, a TandAb, a tandem scFv-Fc, a one-armed tandem scFv-Fc, a DART, a DART-Fc, or a functional fragment thereof. In some embodiments, the IgG antibody construct is an antibody, a variant thereof, or a functional fragment thereof. In some embodiments, the IgG antibody constructs further comprise a constant region, wherein said constant region comprises a first Fc domain and / or a second Fc domain. In some embodiments, said first Fc domain and said second Fc domain are derived from IgGl, IgG2, IgG3 or IgG4. In some embodiments, said first Fc domain and said second Fc domain are derived from IgGl constant domain. In some embodiments, said first Fc domain and said second Fc domain independently comprise M252Y, S254T, and T256E substitutions. In some embodiments, said first Fc domain and said second Fc domain independently comprise L234A and L235A substitutions. In some embodiments, said first Fc domain and said second Fc domain independently comprise P329Gsubstitution. In some embodiments, said first Fc domain comprises a knob modification and said second Fc domain comprises a hole modification, wherein: said knob modification comprises replacing an original amino acid residue from an interface of the Fc region with an amino acid residue selected from tyrosine and tryptophan, and wherein said hole modification comprises replacing an original amino acid residue from the interface of the Fc region with an amino acid residue selected from serine, threonine, valine and alanine. In some embodiments, the first Fc domain comprises at least two modifications at positions selected from L351, F405 and Y407, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, K392 and T394, per EU numbering. In some embodiments, the first Fc domain comprises at least two modifications at positions selected from Q347, Y349, T350, K370, G371, D399 and S400, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T350, S354, E357, K360, Q362E, S364, N390, K409 and T411, per EU numbering. In some embodiments, the first Fc domain comprises at least one substitution at positions selected from S354 and T366, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, L368 and Y407, per EU numbering. In some embodiments, the first Fc domain comprises at least one substitution selected from S354 and T366W, per EU numbering, and the second Fc domain comprises at least one substitution selected from T366S. L368A, Y407T, and Y407V, per EU numbering. In some embodiments, said constant region comprises at least one amino acid modifications, wherein said at least one amino acid modification increases binding affinity of said constant region for a neonatal fragment crystallizable receptor (FcRn) in acidic pH condition relative to said binding affinity of corresponding constant region prior to the at least one amino acid modification, and wherein a binding affinity of said constant region for said FcRn in neutral pH condition remains within 20% of corresponding binding affinity of said corresponding constant region prior to the at least one modification. In some embodiments, said binding affinity of said constant region for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in acidic pH condition relative to the corresponding constant region prior to the at least one modification. In some embodiments, said at least one modification decreases plasma clearance (CL), increases plasma retention time, or increases plasma half-life (t'A) relative to a corresponding IgG antibody construct prior to said at least one modification in said constant region. In some embodiments, a binding affinity of said constant region for a FcRn is increased in neutral pH condition relative to said binding affinity of a corresponding constant region prior to said at least one modification, and wherein a binding affinity of said constant region for said FcRn in acidic pH condition remains within 20% of said binding affinity of corresponding constant region prior to said at least one modification. In some embodiments, said binding affinity of said constant region for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in neutral pH condition relative to said binding affinity of corresponding constant region prior to the at least one modification. In some embodiments, the at least one modification increases plasma clearance of TL1A by the IgGantibody construct, compared to a corresponding plasma clearance by an IgG antibody construct prior to the at least one modification in the constant region.

[0005] Also provided herein are IgG antibody constructs comprising a TL1A binding region that binds an epitope on TL1A, a variant thereof or a functional fragment thereof, and an IL-23 binding region that binds an epitope on IL-23, a variant thereof or a functional fragment thereof, wherein said TL1A binding region comprises a TL1A binding heavy chain variable domain, and wherein said IL-23 binding region comprises an IL-23 binding heavy chain variable domain. In some embodiments, a binding affinity of said TL1A binding region for said TL1A is higher than a binding affinity of said IL- 23 binding region for said IL-23 under neutral pH condition, as measured by surface plasmon resonance spectroscopy. In some embodiments, said binding affinity of said TL1A binding region for said TL1A is at least two times higher than said binding affinity of said IL-23 binding region for said IL-23. In some embodiments, a binding affinity of said IL-23 binding region for said IL-23 is higher than a binding affinity of said TL1A binding region for said TL1A under neutral pH condition, as measured by surface plasmon resonance spectroscopy. In some embodiments, wherein a binding affinity of said IL-23 binding region for said IL-23 is at least two times higher than a binding affinity of said TL1A binding region for said TL1A. In some embodiments, said IgG antibody construct comprises a TL1A binding light chain variable domain that interact with said TL1A binding heavy chain variable domain, thereby forming said TL1A binding region, said TL1A binding heavy chain variable domain and / or said TL1A binding light chain variable domain comprises at least one amino acid modification that (a) increases binding affinity of said TL1A binding region for said TL1A relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification under neutral pH condition, as measured by surface plasmon resonance spectroscopy, and / or (b) decreases binding affinity of said TL1A binding region for said TL1A relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification under acidic pH condition, as measured by surface plasmon resonance spectroscopy. In some embodiments, said IgG antibody construct comprises an IL-23 binding light chain variable domain that interact with said IL-23 binding heavy chain variable domain, thereby forming said IL-23 binding region, said IL-23 binding heavy chain variable domain and / or said IL-23 binding light chain variable domain comprises at least one amino acid modification that (a) increases binding affinity of said IL-23 binding region for said IL-23 relative to said binding affinity of corresponding IL-23 binding region prior to said at least one amino acid modification under neutral pH condition, as measured by surface plasmon resonance spectroscopy, and / or (b) decreases binding affinity of said IL-23 binding region for said IL-23 relative to said binding affinity of corresponding IL-23 binding region prior to said at least one amino acid modification under acidic pH condition, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said TL1A binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-H3 of said TL1A binding heavy chain variable domain. In someembodiments, said at least one amino acid modification comprises a substitution of at least one uncharged amino acid with a charged amino acid. In some embodiments, said at least one amino acid modification is within at least one framework region of said TL1A binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-L1, a CDR- L2, and / or a CDR-L3 of said TL1A binding light chain variable domain. In some embodiments, said at least one amino acid modification is within at least one framework region of said TL1A binding light chain variable domain. In some embodiments, said at least one amino acid modification increases binding affinity of said TL1A binding region for said TL1A in neutral pH condition by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification reduces a binding affinity of said TL1A binding region for said TL1A in acidic pH condition by at least 10% relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said IL-23 binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within at least one framework region of said IL-23 binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-L1, a CDR-L2, and / or a CDR-L3 of said IL-23 binding light chain variable domain. In some embodiments, said at least one amino acid modification is within at least one framework region of said TL1A binding light chain variable domain. In some embodiments, said at least one amino acid modification increases binding affinity of said IL-23 binding region for said IL-23 in neutral pH condition by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to said binding affinity of corresponding IL-23 binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification reduces a binding affinity of said TL1A binding region for said TL1A in acidic pH condition by at least 10% relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said IL- 23 binding heavy chain variable region further binds an epitope that is present on IL-12p40, a variant thereof or a functional fragment thereof. In some embodiments, said IgG antibody construct has higher binding affinity for trimeric TL1A relative to monomeric TL1A under neutral pH condition. In some embodiments, said IgG antibody construct has higher binding affinity for monomeric TL1A relative to trimeric TL1A under neutral pH condition. In some embodiments, said IgG antibody construct has higher binding affinity for monomeric IL-23 relative to heterodimeric IL-23 under neutral pH condition. In some embodiments, said IgG antibody construct has higher binding affinity for heterodimeric IL-23 relative to monomeric IL-23 under neutral pH condition. In some embodiments, said TL1A bindinglight chain variable domain and said IL-23 binding light chain variable domain are at least 90%, at least 95%, at least 98% or 100% identical relative to each other. In some embodiments, said at least one amino acid modification in said TL1A binding heavy chain variable domain increases half-life of said IgG antibody construct in vivo by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to half-life of corresponding IgG antibody construct prior to said at least one amino acid modification. In some embodiments, the IgG antibody construct is an antibody, a Fab2 antibody, a bis-scFv antibody, a diabody, a DVD-Ig, a TandAb, a tandem scFv-Fc, a one-armed tandem scFv-Fc, a DART, a DART-Fc, or a functional fragment thereof. In some embodiments, the IgG antibody construct is an antibody, a variant thereof, or a functional fragment thereof. In some embodiments, the IgG antibody constructs further comprise a constant region, wherein said constant region comprises a first Fc domain and / or a second Fc domain. In some embodiments, said first Fc domain and said second Fc domain are derived from IgGl, IgG2, IgG3 or IgG4. In some embodiments, said first Fc domain and said second Fc domain are derived from IgGl constant domain. In some embodiments, said first Fc domain and said second Fc domain independently comprise M252Y, S254T, and T256E substitutions. In some embodiments, said first Fc domain and said second Fc domain independently comprise L234A and L235A substitutions. In some embodiments, said first Fc domain and said second Fc domain independently comprise P329G substitution. In some embodiments, said first Fc domain comprises a knob modification and said second Fc domain comprises a hole modification, wherein: said knob modification comprises replacing an original amino acid residue from an interface of the Fc region with an amino acid residue selected from tyrosine and tryptophan, and wherein said hole modification comprises replacing an original amino acid residue from the interface of the Fc region with an amino acid residue selected from serine, threonine, valine and alanine. In some embodiments, the first Fc domain comprises at least two modifications at positions selected from L351, F405 and Y407, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, K392 and T394, per EU numbering. In some embodiments, the first Fc domain comprises at least two modifications at positions selected from Q347, Y349, T350, K370, G371, D399 and S400, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T350, S354, E357, K360, Q362E, S364, N390, K409 and T411, per EU numbering. In some embodiments, the first Fc domain comprises at least one substitution at positions selected from S354 and T366, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, L368 and Y407, per EU numbering. In some embodiments, the first Fc domain comprises at least one substitution selected from S354 and T366W, per EU numbering, and the second Fc domain comprises at least one substitution selected from T366S. L368A, Y407T, and Y407V, per EU numbering. In some embodiments, said constant region comprises at least one amino acid modifications, wherein said at least one amino acid modification increases binding affinity of said constant region for a neonatal fragment crystallizable receptor (FcRn) in acidic pH condition relative to said binding affinity of corresponding constant regionprior to the at least one amino acid modification, and wherein a binding affinity of said constant region for said FcRn in neutral pH condition remains within 20% of corresponding binding affinity of said corresponding constant region prior to the at least one modification. In some embodiments, said binding affinity of said constant region for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in acidic pH condition relative to the corresponding constant region prior to the at least one modification. In some embodiments, said at least one modification decreases plasma clearance (CL), increases plasma retention time, or increases plasma half-life (t'A) relative to a corresponding IgG antibody construct prior to said at least one modification in said constant region. In some embodiments, a binding affinity of said constant region for a FcRn is increased in neutral pH condition relative to said binding affinity of a corresponding constant region prior to said at least one modification, and wherein a binding affinity of said constant region for said FcRn in acidic pH condition remains within 20% of said binding affinity of corresponding constant region prior to said at least one modification. In some embodiments, said binding affinity of said constant region for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in neutral pH condition relative to said binding affinity of corresponding constant region prior to the at least one modification. In some embodiments, the at least one modification increases plasma clearance of TL1A by the IgG antibody construct, compared to a corresponding plasma clearance by an IgG antibody construct prior to the at least one modification in the constant region.

[0006] Also provided herein are IgG antibody constructs comprising a TL1A binding region that binds an epitope on TL1A, a variant thereof or a functional fragment thereof, and an IL- 12 binding region that binds an epitope on IL-I2p40, IL-12p35, a variant thereof or a functional fragment thereof, wherein said TL1A binding region comprises a TL1A binding heavy chain variable domain, wherein said IL-12 binding region comprises an IL-12 binding heavy chain variable domain, and wherein a binding affinity of said TL1A binding region for said TL1A is at least 10% higher at pH 7.4 relative to said binding affinity at pH 5.8, as measured by surface plasmon resonance spectroscopy. In some embodiments, a binding affinity of said IL- 12 binding region for said IL- 12 is at least 10% higher at pH 7.4 relative to said binding affinity at pH 5.8, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said TL1A binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-H3 of said TL1A binding heavy chain variable domain. In some embodiments, said at least one amino acid modification comprises a substitution of at least one uncharged amino acid with a charged amino acid. In some embodiments, said at least one amino acid modification is within at least one framework region of said TL1A binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-L1, a CDR- L2, and / or a CDR-L3 of said TL1A binding light chain variable domain. In some embodiments, said at least one amino acid modification is within at least one framework region of said TL1A binding lightchain variable domain. In some embodiments, said at least one amino acid modification increases binding affinity of said TL1A binding region for said TL1A in neutral pH condition by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification reduces a binding affinity of said TL1A binding region for said TL1A in acidic pH condition by at least 10% relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said IL- 12 binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within at least one framework region of said IL- 12 binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-L1, a CDR-L2, and / or a CDR-L3 of said IL-12 binding light chain variable domain. In some embodiments, said at least one amino acid modification increases binding affinity of said IL- 12 binding region for said IL- 12 in neutral pH condition by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to binding affinity of corresponding IL- 12 binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification reduces a binding affinity of said TL1A binding region for said TL1A in acidic pH condition by at least 10% relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said IL- 12 binding heavy chain variable domain further binds an epitope that is present on IL-23, a variant thereof or a functional fragment thereof. In some embodiments, said IgG antibody construct has higher binding affinity for trimeric TL1A relative to monomeric TL1A under neutral pH condition. In some embodiments, said IgG antibody construct has higher binding affinity for monomeric TL1A relative to trimeric TL1A under neutral pH condition. In some embodiments, said TL1A binding light chain variable domain and said IL- 12 binding light chain variable domain are at least 90%, at least 95%, at least 98% or 100% identical relative to each other. In some embodiments, said at least one amino acid modification in said TL1A binding heavy chain variable domain increases half-life of said IgG antibody construct in vivo by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to half-life of corresponding IgG antibody construct prior to said at least one amino acid modification. In some embodiments, the IgG antibody construct is an antibody, a Fab2 antibody, a bis-scFv antibody, a diabody, a DVD-Ig, a TandAb, a tandem scFv-Fc, a one-armed tandem scFv-Fc, a DART, a DART-Fc, or a functional fragment thereof. In some embodiments, the IgG antibody construct is an antibody, a variant thereof, or a functional fragment thereof. In some embodiments, the IgG antibody constructs further comprise a constant region, wherein said constant region comprises a first Fc domain and / or a second Fc domain. In some embodiments,said first Fc domain and said second Fc domain are derived from IgGl, IgG2, IgG3 or IgG4. In some embodiments, said first Fc domain and said second Fc domain are derived from IgGl constant domain. In some embodiments, said first Fc domain and said second Fc domain independently comprise M252Y, S254T, and T256E substitutions. In some embodiments, said first Fc domain and said second Fc domain independently comprise L234A and L235A substitutions. In some embodiments, said first Fc domain and said second Fc domain independently comprise P329G substitution. In some embodiments, said first Fc domain comprises a knob modification and said second Fc domain comprises a hole modification, wherein: said knob modification comprises replacing an original amino acid residue from an interface of the Fc region with an amino acid residue selected from tyrosine and tryptophan, and wherein said hole modification comprises replacing an original amino acid residue from the interface of the Fc region with an amino acid residue selected from serine, threonine, valine and alanine. In some embodiments, the first Fc domain comprises at least two modifications at positions selected from L351, F405 and Y407, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, K392 and T394, per EU numbering. In some embodiments, the first Fc domain comprises at least two modifications at positions selected from Q347, Y349, T350, K370, G371, D399 and S400, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T350, S354, E357, K360, Q362E, S364, N390, K409 and T411, per EU numbering. In some embodiments, the first Fc domain comprises at least one substitution at positions selected from S354 and T366, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, L368 and Y407, per EU numbering. In some embodiments, the first Fc domain comprises at least one substitution selected from S354 and T366W, per EU numbering, and the second Fc domain comprises at least one substitution selected from T366S. L368A, Y407T, and Y407V, per EU numbering. In some embodiments, said constant region comprises at least one amino acid modifications, wherein said at least one amino acid modification increases binding affinity of said constant region for a neonatal fragment crystallizable receptor (FcRn) in acidic pH condition relative to said binding affinity of corresponding constant region prior to the at least one amino acid modification, and wherein a binding affinity of said constant region for said FcRn in neutral pH condition remains within 20% of corresponding binding affinity of said corresponding constant region prior to the at least one modification. In some embodiments, said binding affinity of said constant region for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in acidic pH condition relative to the corresponding constant region prior to the at least one modification. In some embodiments, said at least one modification decreases plasma clearance (CL), increases plasma retention time, or increases plasma half-life (t'A) relative to a corresponding IgG antibody construct prior to said at least one modification in said constant region. In some embodiments, a binding affinity of said constant region for a FcRn is increased in neutral pH condition relative to said binding affinity of a corresponding constant region prior to said at least one modification, and wherein a binding affinity of said constant region for saidFcRn in acidic pH condition remains within 20% of said binding affinity of corresponding constant region prior to said at least one modification. In some embodiments, said binding affinity of said constant region for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in neutral pH condition relative to said binding affinity of corresponding constant region prior to the at least one modification. In some embodiments, the at least one modification increases plasma clearance of TL1A by the IgG antibody construct, compared to a corresponding plasma clearance by an IgG antibody construct prior to the at least one modification in the constant region.

[0007] Also provided herein are IgG antibody constructs comprising a TL1A binding region that binds an epitope on TL1A, a variant thereof or a functional fragment thereof, and an IL- 12 binding region that binds an epitope on IL-I2p40, IL-12p35, a variant thereof or a functional fragment thereof, wherein said TL1A binding region comprises a TL1A binding heavy chain variable domain, wherein said IL-12 binding region comprises an IL-12 binding heavy chain variable domain, and wherein a binding affinity of the TL1A binding region for said TL1A is more than four times a binding affinity of the IL- 12 binding region for said IL- 12 under neutral pH condition, as measured by surface plasmon resonance spectroscopy. In some embodiments, a binding affinity of the IL-12 binding region for said IL- 12 is at least two times higher than a binding affinity of the TL1A binding region for said TL1A. In some embodiments, said IgG antibody construct comprises a TL1A binding light chain variable domain that interact with said TL1A binding heavy chain variable domain, thereby forming said TL1A binding region, said TL1A binding heavy chain variable domain and / or said TL1A binding light chain variable domain comprises at least one amino acid modification that (a) increases binding affinity of said TL1A binding region for said TL1A relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification under neutral pH condition, as measured by surface plasmon resonance spectroscopy, and / or (b) decreases binding affinity of said TL1A binding region for said TL1A relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification under acidic pH condition, as measured by surface plasmon resonance spectroscopy. In some embodiments, said IgG antibody construct comprises an IL- 12 binding light chain variable domain that interact with said IL- 12 binding heavy chain variable domain, thereby forming said IL- 12 binding region, said IL- 12 binding heavy chain variable domain and / or said IL- 12 binding light chain variable domain comprises at least one amino acid modification that (a) increases binding affinity of said IL-12 binding region for said IL-12 relative to said binding affinity of corresponding IL- 12 binding region prior to said at least one amino acid modification under neutral pH condition, as measured by surface plasmon resonance spectroscopy, and / or (b) decreases binding affinity of said IL- 12 binding region for said IL- 12 relative to said binding affinity of corresponding IL- 12 binding region prior to said at least one amino acid modification under acidic pH condition, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said TL1A bindingheavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-H3 of said TL1A binding heavy chain variable domain. In some embodiments, said at least one amino acid modification comprises a substitution of at least one uncharged amino acid with a charged amino acid. In some embodiments, said at least one amino acid modification is within at least one framework region of said TL1A binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-L1, a CDR-L2, and / or a CDR-L3 of said TL1A binding light chain variable domain. In some embodiments, said at least one amino acid modification is within at least one framework region of said TL1A binding light chain variable domain. In some embodiments, said at least one amino acid modification increases binding affinity of said TL1A binding region for said TL1A in neutral pH condition by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification reduces a binding affinity of said TL1A binding region for said TL1A in acidic pH condition by at least 10% relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said IL-12 binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within at least one framework region of said IL- 12 binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-L1, a CDR-L2, and / or a CDR- L3 of said IL-12 binding light chain variable domain. In some embodiments, said at least one amino acid modification increases binding affinity of said IL- 12 binding region for said IL- 12 in neutral pH condition by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to binding affinity of corresponding IL-12 binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification reduces a binding affinity of said TL1A binding region for said TL1A in acidic pH condition by at least 10% relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said IL-12 binding heavy chain variable domain further binds an epitope that is present on IL-23, a variant thereof or a functional fragment thereof. In some embodiments, said IgG antibody construct has higher binding affinity for trimeric TL1A relative to monomeric TL1A under neutral pH condition. In some embodiments, said IgG antibody construct has higher binding affinity for monomeric TL1A relative to trimeric TL1A under neutral pH condition. In some embodiments, said TL1A binding light chain variable domain and said IL-12 binding light chain variable domain are at least 90%, at least 95%, at least 98% or 100% identical relative to each other. In some embodiments, said at least one amino acid modification in said TL1A binding heavy chain variable domain increases half-life of said IgG antibody construct in vivoby at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to half-life of corresponding IgG antibody construct prior to said at least one amino acid modification. In some embodiments, the IgG antibody construct is an antibody, a Fab2 antibody, a bis-scFv antibody, a diabody, a DVD-Ig, a TandAb, a tandem scFv-Fc, a one-armed tandem scFv-Fc, a DART, a DART-Fc, or a functional fragment thereof. In some embodiments, the IgG antibody construct is an antibody, a variant thereof, or a functional fragment thereof. In some embodiments, the IgG antibody constructs further comprise a constant region, wherein said constant region comprises a first Fc domain and / or a second Fc domain. In some embodiments, said first Fc domain and said second Fc domain are derived from IgGl, IgG2, IgG3 or IgG4. In some embodiments, said first Fc domain and said second Fc domain are derived from IgGl constant domain. In some embodiments, said first Fc domain and said second Fc domain independently comprise M252Y, S254T, and T256E substitutions. In some embodiments, said first Fc domain and said second Fc domain independently comprise L234A and L235A substitutions. In some embodiments, said first Fc domain and said second Fc domain independently comprise P329G substitution. In some embodiments, said first Fc domain comprises a knob modification and said second Fc domain comprises a hole modification, wherein: said knob modification comprises replacing an original amino acid residue from an interface of the Fc region with an amino acid residue selected from tyrosine and tryptophan, and wherein said hole modification comprises replacing an original amino acid residue from the interface of the Fc region with an amino acid residue selected from serine, threonine, valine and alanine. In some embodiments, the first Fc domain comprises at least two modifications at positions selected from L351, F405 and Y407, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, K392 and T394, per EU numbering. In some embodiments, the first Fc domain comprises at least two modifications at positions selected from Q347, Y349, T350, K370, G371, D399 and S400, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T350, S354, E357, K360, Q362E, S364, N390, K409 and T411, per EU numbering. In some embodiments, the first Fc domain comprises at least one substitution at positions selected from S354 and T366, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, L368 and Y407, per EU numbering. In some embodiments, the first Fc domain comprises at least one substitution selected from S354 and T366W, per EU numbering, and the second Fc domain comprises at least one substitution selected from T366S. L368A, Y407T, and Y407V, per EU numbering. In some embodiments, said constant region comprises at least one amino acid modifications, wherein said at least one amino acid modification increases binding affinity of said constant region for a neonatal fragment crystallizable receptor (FcRn) in acidic pH condition relative to said binding affinity of corresponding constant region prior to the at least one amino acid modification, and wherein a binding affinity of said constant region for said FcRn in neutral pH condition remains within 20% of corresponding binding affinity of said corresponding constant region prior to the at least one modification. In some embodiments, said binding affinity of said constantregion for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in acidic pH condition relative to the corresponding constant region prior to the at least one modification. In some embodiments, said at least one modification decreases plasma clearance (CL), increases plasma retention time, or increases plasma half-life (t'A) relative to a corresponding IgG antibody construct prior to said at least one modification in said constant region. In some embodiments, a binding affinity of said constant region for a FcRn is increased in neutral pH condition relative to said binding affinity of a corresponding constant region prior to said at least one modification, and wherein a binding affinity of said constant region for said FcRn in acidic pH condition remains within 20% of said binding affinity of corresponding constant region prior to said at least one modification. In some embodiments, said binding affinity of said constant region for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in neutral pH condition relative to said binding affinity of corresponding constant region prior to the at least one modification. In some embodiments, the at least one modification increases plasma clearance of TL1A by the IgG antibody construct, compared to a corresponding plasma clearance by an IgG antibody construct prior to the at least one modification in the constant region.

[0008] Also provided herein are IgG antibody constructs comprising a TL1A binding region that binds an epitope on TL1A, a variant thereof or a functional fragment thereof, and an IL- 12 binding region that binds an epitope on IL-12p40, IL-12p35, a variant thereof or a functional fragment thereof, wherein said TL1A binding region comprises a TL1A binding heavy chain variable domain, wherein said IL-12 binding region comprises an IL-12 binding heavy chain variable domain, and wherein a binding affinity of the IL- 12 binding region for said IL- 12 is higher than a binding affinity of the TL1A binding region for said TL1A under neutral pH condition, as measured by surface plasmon resonance spectroscopy. In some embodiments, a binding affinity of the IL- 12 binding region for said IL- 12 is at least two times higher than a binding affinity of the TL1A binding region for said TL1A. In some embodiments, said IgG antibody construct comprises a TL1A binding light chain variable domain that interact with said TL1A binding heavy chain variable domain, thereby forming said TL1A binding region, said TL1A binding heavy chain variable domain and / or said TL1A binding light chain variable domain comprises at least one amino acid modification that (a) increases binding affinity of said TL1A binding region for said TL1A relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification under neutral pH condition, as measured by surface plasmon resonance spectroscopy, and / or (b) decreases binding affinity of said TL1A binding region for said TL1A relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification under acidic pH condition, as measured by surface plasmon resonance spectroscopy. In some embodiments, said IgG antibody construct comprises an IL-12 binding light chain variable domain that interact with said IL- 12 binding heavy chain variable domain, thereby forming said IL- 12 binding region, said IL- 12 binding heavy chain variable domain and / or said IL- 12binding light chain variable domain comprises at least one amino acid modification that (a) increases binding affinity of said IL- 12 binding region for said IL- 12 relative to said binding affinity of corresponding IL- 12 binding region prior to said at least one amino acid modification under neutral pH condition, as measured by surface plasmon resonance spectroscopy, and / or (b) decreases binding affinity of said IL- 12 binding region for said IL- 12 relative to said binding affinity of corresponding IL- 12 binding region prior to said at least one amino acid modification under acidic pH condition, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said TL1A binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-H3 of said TL1A binding heavy chain variable domain. In some embodiments, said at least one amino acid modification comprises a substitution of at least one uncharged amino acid with a charged amino acid. In some embodiments, said at least one amino acid modification is within at least one framework region of said TL1A binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-L1, a CDR-L2, and / or a CDR-L3 of said TL1A binding light chain variable domain. In some embodiments, said at least one amino acid modification is within at least one framework region of said TL1A binding light chain variable domain. In some embodiments, said at least one amino acid modification increases binding affinity of said TL1A binding region for said TL1A in neutral pH condition by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification reduces a binding affinity of said TL1A binding region for said TL1A in acidic pH condition by at least 10% relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said IL- 12 binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within at least one framework region of said IL- 12 binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-L1, a CDR-L2, and / or a CDR- L3 of said IL-12 binding light chain variable domain. In some embodiments, said at least one amino acid modification increases binding affinity of said IL- 12 binding region for said IL- 12 in neutral pH condition by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to binding affinity of corresponding IL-12 binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification reduces a binding affinity of said TL1A binding region for said TL1A in acidic pH condition by at least 10% relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said IL-12 binding heavy chainvariable domain further binds an epitope that is present on IL-23, a variant thereof or a functional fragment thereof. In some embodiments, said IgG antibody construct has higher binding affinity for trimeric TL1A relative to monomeric TL1A under neutral pH condition. In some embodiments, said IgG antibody construct has higher binding affinity for monomeric TL1A relative to trimeric TL1A under neutral pH condition. In some embodiments, said TL1A binding light chain variable domain and said IL-12 binding light chain variable domain are at least 90%, at least 95%, at least 98% or 100% identical relative to each other. In some embodiments, said at least one amino acid modification in said TL1A binding heavy chain variable domain increases half-life of said IgG antibody construct in vivo by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to half-life of corresponding IgG antibody construct prior to said at least one amino acid modification. In some embodiments, the IgG antibody construct is an antibody, a Fab2 antibody, a bis-scFv antibody, a diabody, a DVD-Ig, a TandAb, a tandem scFv-Fc, a one-armed tandem scFv-Fc, a DART, a DART-Fc, or a functional fragment thereof. In some embodiments, the IgG antibody construct is an antibody, a variant thereof, or a functional fragment thereof. In some embodiments, the IgG antibody constructs further comprise a constant region, wherein said constant region comprises a first Fc domain and / or a second Fc domain. In some embodiments, said first Fc domain and said second Fc domain are derived from IgGl, IgG2, IgG3 or IgG4. In some embodiments, said first Fc domain and said second Fc domain are derived from IgGl constant domain. In some embodiments, said first Fc domain and said second Fc domain independently comprise M252Y, S254T, and T256E substitutions. In some embodiments, said first Fc domain and said second Fc domain independently comprise L234A and L235A substitutions. In some embodiments, said first Fc domain and said second Fc domain independently comprise P329G substitution. In some embodiments, said first Fc domain comprises a knob modification and said second Fc domain comprises a hole modification, wherein: said knob modification comprises replacing an original amino acid residue from an interface of the Fc region with an amino acid residue selected from tyrosine and tryptophan, and wherein said hole modification comprises replacing an original amino acid residue from the interface of the Fc region with an amino acid residue selected from serine, threonine, valine and alanine. In some embodiments, the first Fc domain comprises at least two modifications at positions selected from L351, F405 and Y407, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, K392 and T394, per EU numbering. In some embodiments, the first Fc domain comprises at least two modifications at positions selected from Q347, Y349, T350, K370, G371, D399 and S400, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T350, S354, E357, K360, Q362E, S364, N390, K409 and T411, per EU numbering. In some embodiments, the first Fc domain comprises at least one substitution at positions selected from S354 and T366, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, L368 and Y407, per EU numbering. In some embodiments, the first Fc domain comprises at least one substitution selected from S354 and T366W,per EU numbering, and the second Fc domain comprises at least one substitution selected from T366S. L368A, Y407T, and Y407V, per EU numbering. In some embodiments, said constant region comprises at least one amino acid modifications, wherein said at least one amino acid modification increases binding affinity of said constant region for a neonatal fragment crystallizable receptor (FcRn) in acidic pH condition relative to said binding affinity of corresponding constant region prior to the at least one amino acid modification, and wherein a binding affinity of said constant region for said FcRn in neutral pH condition remains within 20% of corresponding binding affinity of said corresponding constant region prior to the at least one modification. In some embodiments, said binding affinity of said constant region for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in acidic pH condition relative to the corresponding constant region prior to the at least one modification. In some embodiments, said at least one modification decreases plasma clearance (CL), increases plasma retention time, or increases plasma half-life (t'A) relative to a corresponding IgG antibody construct prior to said at least one modification in said constant region. In some embodiments, a binding affinity of said constant region for a FcRn is increased in neutral pH condition relative to said binding affinity of a corresponding constant region prior to said at least one modification, and wherein a binding affinity of said constant region for said FcRn in acidic pH condition remains within 20% of said binding affinity of corresponding constant region prior to said at least one modification. In some embodiments, said binding affinity of said constant region for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in neutral pH condition relative to said binding affinity of corresponding constant region prior to the at least one modification. In some embodiments, the at least one modification increases plasma clearance of TL1A by the IgG antibody construct, compared to a corresponding plasma clearance by an IgG antibody construct prior to the at least one modification in the constant region.

[0009] Also provided herein are IgG antibody constructs comprising a TL1A binding region that binds an epitope on TL1A, a variant thereof or a functional fragment thereof, and a second binding region that binds a second epitope on IL-6R, IL-6, IL- 17 family cytokine, IL-17R, a variant thereof or a functional fragment thereof, wherein said TL1A binding region comprises a TL1A binding heavy chain variable domain and a TL1A binding light chain variable domain, wherein at least one amino acid modification in said TL1A binding heavy chain variable domain and / or said TL1A binding light chain variable domain, and wherein said amino acid modification changes an isoelectric point (pl) of said IgG antibody construct relative to a pl of a corresponding IgG antibody construct prior to said amino acid modification, thereby resulting in pH-dependent binding activity for said TL1A in said IgG antibody construct, as measured by surface plasmon resonance spectroscopy. In some embodiments, said second binding region comprises a second binding heavy chain variable domain and a second binding light chain variable domain, and at least one amino acid modification in said second binding heavy chain variable domain and / or said second binding light chain variable domain, wherein said amino acidmodification changes an isoelectric point (pl) of said IgG antibody construct relative to a pl of a corresponding IgG antibody construct prior to said amino acid modification, thereby resulting in pH- dependent binding activity for said second epitope in said IgG antibody construct, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said TL1A binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-H3 of said TL1A binding heavy chain variable domain. In some embodiments, said at least one amino acid modification comprises a substitution of at least one uncharged amino acid with a charged amino acid. In some embodiments, said at least one amino acid modification is within at least one framework region of said second binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-L1, a CDR-L2, and / or a CDR-L3 of said second binding light chain variable domain. In some embodiments, said at least one amino acid modification is within at least one framework region of said second binding light chain variable domain. In some embodiments, said at least one amino acid modification increases binding affinity of said TL1A binding region for said TL1A in neutral pH condition by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification reduces binding affinity of said TL1A binding region for said TL1A in acidic pH condition by at least 10% relative to binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said second binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within at least one framework region of said second binding heavy chain variable domain. In some embodiments, said IgG antibody construct has higher binding affinity for trimeric TL1A relative to monomeric TL1A under neutral pH condition. In some embodiments, said IgG antibody construct has higher binding affinity for monomeric TL1A relative to trimeric TL1A under neutral pH condition. In some embodiments, said TL1A binding light chain variable domain and said second binding light chain variable domain are at least 90%, at least 95%, at least 98% or 100% identical relative to each other. In some embodiments, said at least one amino acid modification in said TL1A binding heavy chain variable domain increases half-life of said IgG antibody construct in vivo by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to halflife of corresponding IgG antibody construct prior to said at least one amino acid modification. In some embodiments, the IgG antibody construct is an antibody, a Fab2 antibody, a bis-scFv antibody, a diabody, a DVD-Ig, a TandAb, a tandem scFv-Fc, a one-armed tandem scFv-Fc, a DART, a DART-Fc, or a functional fragment thereof. In some embodiments, the IgG antibody construct is an antibody, a variant thereof, or a functional fragment thereof. In some embodiments, the IgG antibody constructsfurther comprise a constant region, wherein said constant region comprises a first Fc domain and / or a second Fc domain. In some embodiments, said first Fc domain and said second Fc domain are derived from IgGl, IgG2, IgG3 or IgG4. In some embodiments, said first Fc domain and said second Fc domain are derived from IgGl constant domain. In some embodiments, said first Fc domain and said second Fc domain independently comprise M252Y, S254T, and T256E substitutions. In some embodiments, said first Fc domain and said second Fc domain independently comprise L234A and L235A substitutions. In some embodiments, said first Fc domain and said second Fc domain independently comprise P329G substitution. In some embodiments, said first Fc domain comprises a knob modification and said second Fc domain comprises a hole modification, wherein: said knob modification comprises replacing an original amino acid residue from an interface of the Fc region with an amino acid residue selected from tyrosine and tryptophan, and wherein said hole modification comprises replacing an original amino acid residue from the interface of the Fc region with an amino acid residue selected from serine, threonine, valine and alanine. In some embodiments, the first Fc domain comprises at least two modifications at positions selected from L351, F405 and Y407, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, K392 and T394, per EU numbering. In some embodiments, the first Fc domain comprises at least two modifications at positions selected from Q347, Y349, T350, K370, G371, D399 and S400, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T350, S354, E357, K360, Q362E, S364, N390, K409 and T411, per EU numbering. In some embodiments, the first Fc domain comprises at least one substitution at positions selected from S354 and T366, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, L368 and Y407, per EU numbering. In some embodiments, the first Fc domain comprises at least one substitution selected from S354 and T366W, per EU numbering, and the second Fc domain comprises at least one substitution selected from T366S. L368A, Y407T, and Y407V, per EU numbering. In some embodiments, said constant region comprises at least one amino acid modifications, wherein said at least one amino acid modification increases binding affinity of said constant region for a neonatal fragment crystallizable receptor (FcRn) in acidic pH condition relative to said binding affinity of corresponding constant region prior to the at least one amino acid modification, and wherein a binding affinity of said constant region for said FcRn in neutral pH condition remains within 20% of corresponding binding affinity of said corresponding constant region prior to the at least one modification. In some embodiments, said binding affinity of said constant region for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in acidic pH condition relative to the corresponding constant region prior to the at least one modification. In some embodiments, said at least one modification decreases plasma clearance (CL), increases plasma retention time, or increases plasma half-life (t'A) relative to a corresponding IgG antibody construct prior to said at least one modification in said constant region. In some embodiments, a binding affinity of said constant region for a FcRn is increased in neutral pH condition relative to said binding affinity of a correspondingconstant region prior to said at least one modification, and wherein a binding affinity of said constant region for said FcRn in acidic pH condition remains within 20% of said binding affinity of corresponding constant region prior to said at least one modification. In some embodiments, said binding affinity of said constant region for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in neutral pH condition relative to said binding affinity of corresponding constant region prior to the at least one modification. In some embodiments, the at least one modification increases plasma clearance of TL1A by the IgG antibody construct, compared to a corresponding plasma clearance by an IgG antibody construct prior to the at least one modification in the constant region.

[0010] Also provided herein are IgG antibody constructs comprising a TL1A binding region that binds an epitope on TL1A, a variant thereof or a functional fragment thereof, and a second binding region that binds a second epitope on IL-6R, IL-6, IL- 17 family cytokine, IL-17R, a variant thereof or a functional fragment thereof, wherein said TL1A binding region comprises a TL1A binding heavy chain variable domain, wherein said second binding region comprises a second binding heavy chain variable domain, and wherein a binding affinity of said TL1A binding region for said TL1A is at least 10% higher at pH 7.4 relative to said binding affinity at pH 5.8, as measured by surface plasmon resonance spectroscopy. In some embodiments, a binding affinity of said second binding region for said second epitope is at least 10% higher at pH 7.4 relative to said binding affinity at pH 5.8, as measured by surface plasmon resonance spectroscopy. In some embodiments, said IgG antibody construct comprises a TL1A binding light chain variable domain that interact with said TL1A binding heavy chain variable domain, thereby forming said TL1A binding region, said TL1A binding heavy chain variable domain and / or said TL1A binding light chain variable domain comprises at least one amino acid modification that (a) increases binding affinity of said TL1A binding region for said TL1 A relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification under neutral pH condition, as measured by surface plasmon resonance spectroscopy, and / or (b) decreases binding affinity of said TL1A binding region for said TL1A relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification under acidic pH condition, as measured by surface plasmon resonance spectroscopy. In some embodiments, said IgG antibody construct comprises a second binding light chain variable domain that interact with said second binding heavy chain variable domain, thereby forming said second binding region, said second binding heavy chain variable domain and / or said second binding light chain variable domain comprises at least one amino acid modification that (a) increases binding affinity of said second binding region second epitope relative to said binding affinity of corresponding second binding region prior to said at least one amino acid modification under neutral pH condition, as measured by surface plasmon resonance spectroscopy, and / or (b) decreases binding affinity of said second binding region second epitope relative to said binding affinity of corresponding second binding region prior to said at least one amino acid modification under acidic pH condition, as measured by surface plasmon resonancespectroscopy. In some embodiments, said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said TL1A binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-H3 of said TL1A binding heavy chain variable domain. In some embodiments, said at least one amino acid modification comprises a substitution of at least one uncharged amino acid with a charged amino acid. In some embodiments, said at least one amino acid modification is within at least one framework region of said second binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-L1, a CDR-L2, and / or a CDR-L3 of said second binding light chain variable domain. In some embodiments, said at least one amino acid modification is within at least one framework region of said second binding light chain variable domain. In some embodiments, said at least one amino acid modification increases binding affinity of said TL1A binding region for said TL1A in neutral pH condition by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification reduces binding affinity of said TL1A binding region for said TL1A in acidic pH condition by at least 10% relative to binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said second binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within at least one framework region of said second binding heavy chain variable domain. In some embodiments, said IgG antibody construct has higher binding affinity for trimeric TL1A relative to monomeric TL1A under neutral pH condition. In some embodiments, said IgG antibody construct has higher binding affinity for monomeric TL1A relative to trimeric TL1A under neutral pH condition. In some embodiments, said TL1A binding light chain variable domain and said second binding light chain variable domain are at least 90%, at least 95%, at least 98% or 100% identical relative to each other. In some embodiments, said at least one amino acid modification in said TL1A binding heavy chain variable domain increases half-life of said IgG antibody construct in vivo by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to half-life of corresponding IgG antibody construct prior to said at least one amino acid modification. In some embodiments, the IgG antibody construct is an antibody, a Fab2 antibody, a bis-scFv antibody, a diabody, a DVD-Ig, a TandAb, a tandem scFv-Fc, a one-armed tandem scFv-Fc, a DART, a DART-Fc, or a functional fragment thereof. In some embodiments, the IgG antibody construct is an antibody, a variant thereof, or a functional fragment thereof. In some embodiments, the IgG antibody constructs further comprise a constant region, wherein said constant region comprises a first Fc domain and / or a second Fc domain. In some embodiments, said first Fc domain and said second Fc domain are derived from IgGl, IgG2, IgG3 or IgG4. In some embodiments, said first Fc domain and said second Fc domain are derived from IgGlconstant domain. In some embodiments, said first Fc domain and said second Fc domain independently comprise M252Y, S254T, and T256E substitutions. In some embodiments, said first Fc domain and said second Fc domain independently comprise L234A and L235A substitutions. In some embodiments, said first Fc domain and said second Fc domain independently comprise P329G substitution. In some embodiments, said first Fc domain comprises a knob modification and said second Fc domain comprises a hole modification, wherein: said knob modification comprises replacing an original amino acid residue from an interface of the Fc region with an amino acid residue selected from tyrosine and tryptophan, and wherein said hole modification comprises replacing an original amino acid residue from the interface of the Fc region with an amino acid residue selected from serine, threonine, valine and alanine. In some embodiments, the first Fc domain comprises at least two modifications at positions selected from L351, F405 and Y407, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, K392 and T394, per EU numbering. In some embodiments, the first Fc domain comprises at least two modifications at positions selected from Q347, Y349, T350, K370, G371, D399 and S400, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T350, S354, E357, K360, Q362E, S364, N390, K409 and T411, per EU numbering. In some embodiments, the first Fc domain comprises at least one substitution at positions selected from S354 and T366, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, L368 and Y407, per EU numbering. In some embodiments, the first Fc domain comprises at least one substitution selected from S354 and T366W, per EU numbering, and the second Fc domain comprises at least one substitution selected from T366S. L368A, Y407T, and Y407V, per EU numbering. In some embodiments, said constant region comprises at least one amino acid modifications, wherein said at least one amino acid modification increases binding affinity of said constant region for a neonatal fragment crystallizable receptor (FcRn) in acidic pH condition relative to said binding affinity of corresponding constant region prior to the at least one amino acid modification, and wherein a binding affinity of said constant region for said FcRn in neutral pH condition remains within 20% of corresponding binding affinity of said corresponding constant region prior to the at least one modification. In some embodiments, said binding affinity of said constant region for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in acidic pH condition relative to the corresponding constant region prior to the at least one modification. In some embodiments, said at least one modification decreases plasma clearance (CL), increases plasma retention time, or increases plasma half-life (t'A) relative to a corresponding IgG antibody construct prior to said at least one modification in said constant region. In some embodiments, a binding affinity of said constant region for a FcRn is increased in neutral pH condition relative to said binding affinity of a corresponding constant region prior to said at least one modification, and wherein a binding affinity of said constant region for said FcRn in acidic pH condition remains within 20% of said binding affinity of corresponding constant region prior to said at least one modification. In some embodiments, saidbinding affinity of said constant region for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in neutral pH condition relative to said binding affinity of corresponding constant region prior to the at least one modification. In some embodiments, the at least one modification increases plasma clearance of TL1A by the IgG antibody construct, compared to a corresponding plasma clearance by an IgG antibody construct prior to the at least one modification in the constant region.

[0011] Also provided herein are IgG antibody constructs comprising a TL1A binding region that binds an epitope on TL1A, a variant thereof or a functional fragment thereof, and an second binding region that binds a second epitope on IL-6R, IL-6, IL- 17 family cytokine, IL-17R, a variant thereof or a functional fragment thereof, wherein said TL1A binding region comprises a TL1A binding heavy chain variable domain, and wherein said second binding region comprises a second binding heavy chain variable domain. In some embodiments, a binding affinity of said TL1A binding region for said TL1A is higher than a binding affinity of said second binding region for said second epitope under neutral pH condition, as measured by surface plasmon resonance spectroscopy. In some embodiments, said binding affinity of said TL1A binding region for said TL1A is at least two times higher than said binding affinity of said second binding region for said second epitope. In some embodiments, a binding affinity of said second binding region for said second epitope is higher than a binding affinity of said TL1A binding region for said TL1A under neutral pH condition, as measured by surface plasmon resonance spectroscopy. In some embodiments, a binding affinity of said second binding region for said second epitope is at least two times higher than a binding affinity of said TL1A binding region for said TL1A. In some embodiments, said IgG antibody construct comprises a TL1A binding light chain variable domain that interact with said TL1A binding heavy chain variable domain, thereby forming said TL1A binding region, said TL1A binding heavy chain variable domain and / or said TL1A binding light chain variable domain comprises at least one amino acid modification that (a) increases binding affinity of said TL1A binding region for said TL1A relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification under neutral pH condition, as measured by surface plasmon resonance spectroscopy, and / or (b) decreases binding affinity of said TL1A binding region for said TL1A relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification under acidic pH condition, as measured by surface plasmon resonance spectroscopy. In some embodiments, said IgG antibody construct comprises a second binding light chain variable domain that interact with said second binding heavy chain variable domain, thereby forming said second binding region, said second binding heavy chain variable domain and / or said second binding light chain variable domain comprises at least one amino acid modification that (a) increases binding affinity of said second binding region second epitope relative to said binding affinity of corresponding second binding region prior to said at least one amino acid modification under neutral pH condition, as measured by surface plasmon resonance spectroscopy, and / or (b) decreases binding affinity of said second binding region second epitope relative to said binding affinity ofcorresponding second binding region prior to said at least one amino acid modification under acidic pH condition, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said TL1A binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-H3 of said TL1A binding heavy chain variable domain. In some embodiments, said at least one amino acid modification comprises a substitution of at least one uncharged amino acid with a charged amino acid. In some embodiments, said at least one amino acid modification is within at least one framework region of said second binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within a CDR-L1, a CDR-L2, and / or a CDR-L3 of said second binding light chain variable domain. In some embodiments, said at least one amino acid modification is within at least one framework region of said second binding light chain variable domain. In some embodiments, said at least one amino acid modification increases binding affinity of said TL1A binding region for said TL1A in neutral pH condition by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification reduces binding affinity of said TL1A binding region for said TL1A in acidic pH condition by at least 10% relative to binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy. In some embodiments, said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said second binding heavy chain variable domain. In some embodiments, said at least one amino acid modification is within at least one framework region of said second binding heavy chain variable domain. In some embodiments, said IgG antibody construct has higher binding affinity for trimeric TL1A relative to monomeric TL1A under neutral pH condition. In some embodiments, said IgG antibody construct has higher binding affinity for monomeric TL1A relative to trimeric TL1A under neutral pH condition. In some embodiments, said TL1A binding light chain variable domain and said second binding light chain variable domain are at least 90%, at least 95%, at least 98% or 100% identical relative to each other. In some embodiments, said at least one amino acid modification in said TL1A binding heavy chain variable domain increases half-life of said IgG antibody construct in vivo by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to halflife of corresponding IgG antibody construct prior to said at least one amino acid modification. In some embodiments, the IgG antibody construct is an antibody, a Fab2 antibody, a bis-scFv antibody, a diabody, a DVD-Ig, a TandAb, a tandem scFv-Fc, a one-armed tandem scFv-Fc, a DART, a DART-Fc, or a functional fragment thereof. In some embodiments, the IgG antibody construct is an antibody, a variant thereof, or a functional fragment thereof. In some embodiments, the IgG antibody constructs further comprise a constant region, wherein said constant region comprises a first Fc domain and / or a second Fc domain. In some embodiments, said first Fc domain and said second Fc domain are derivedfrom IgGl, IgG2, IgG3 or IgG4. In some embodiments, said first Fc domain and said second Fc domain are derived from IgGl constant domain. In some embodiments, said first Fc domain and said second Fc domain independently comprise M252Y, S254T, and T256E substitutions. In some embodiments, said first Fc domain and said second Fc domain independently comprise L234A and L235A substitutions. In some embodiments, said first Fc domain and said second Fc domain independently comprise P329G substitution. In some embodiments, said first Fc domain comprises a knob modification and said second Fc domain comprises a hole modification, wherein: said knob modification comprises replacing an original amino acid residue from an interface of the Fc region with an amino acid residue selected from tyrosine and tryptophan, and wherein said hole modification comprises replacing an original amino acid residue from the interface of the Fc region with an amino acid residue selected from serine, threonine, valine and alanine. In some embodiments, the first Fc domain comprises at least two modifications at positions selected from L351, F405 and Y407, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, K392 and T394, per EU numbering. In some embodiments, the first Fc domain comprises at least two modifications at positions selected from Q347, Y349, T350, K370, G371, D399 and S400, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T350, S354, E357, K360, Q362E, S364, N390, K409 and T411, per EU numbering. In some embodiments, the first Fc domain comprises at least one substitution at positions selected from S354 and T366, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, L368 and Y407, per EU numbering. In some embodiments, the first Fc domain comprises at least one substitution selected from S354 and T366W, per EU numbering, and the second Fc domain comprises at least one substitution selected from T366S. L368A, Y407T, and Y407V, per EU numbering. In some embodiments, said constant region comprises at least one amino acid modifications, wherein said at least one amino acid modification increases binding affinity of said constant region for a neonatal fragment crystallizable receptor (FcRn) in acidic pH condition relative to said binding affinity of corresponding constant region prior to the at least one amino acid modification, and wherein a binding affinity of said constant region for said FcRn in neutral pH condition remains within 20% of corresponding binding affinity of said corresponding constant region prior to the at least one modification. In some embodiments, said binding affinity of said constant region for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in acidic pH condition relative to the corresponding constant region prior to the at least one modification. In some embodiments, said at least one modification decreases plasma clearance (CL), increases plasma retention time, or increases plasma half-life (t'A) relative to a corresponding IgG antibody construct prior to said at least one modification in said constant region. In some embodiments, a binding affinity of said constant region for a FcRn is increased in neutral pH condition relative to said binding affinity of a corresponding constant region prior to said at least one modification, and wherein a binding affinity of said constant region for said FcRn in acidic pH condition remains within 20% of said binding affinity ofcorresponding constant region prior to said at least one modification. In some embodiments, said binding affinity of said constant region for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in neutral pH condition relative to said binding affinity of corresponding constant region prior to the at least one modification. In some embodiments, the at least one modification increases plasma clearance of TL1A by the IgG antibody construct, compared to a corresponding plasma clearance by an IgG antibody construct prior to the at least one modification in the constant region.

[0012] In some embodiments, the IgG antibody construct is an antibody, a Fab2 antibody, a bis-scFv antibody, a diabody, a DVD-Ig, a TandAb, a tandem scFv-Fc, a one-armed tandem scFv-Fc, a DART, a DART-Fc, or a functional fragment thereof. In some embodiments, the IgG antibody construct is an antibody, a variant thereof, or a functional fragment thereof. In some embodiments, the IgG antibody constructs further comprise a constant region, wherein said constant region comprises a first Fc domain and / or a second Fc domain. In some embodiments, said first Fc domain and said second Fc domain are derived from IgGl, IgG2, IgG3 or IgG4. In some embodiments, said first Fc domain and said second Fc domain are derived from IgGl constant domain. In some embodiments, said first Fc domain and said second Fc domain independently comprise M252Y, S254T, and T256E substitutions. In some embodiments, said first Fc domain and said second Fc domain independently comprise L234A and L235A substitutions. In some embodiments, said first Fc domain and said second Fc domain independently comprise P329G substitution. In some embodiments, said first Fc domain comprises a knob modification and said second Fc domain comprises a hole modification, wherein: said knob modification comprises replacing an original amino acid residue from an interface of the Fc region with an amino acid residue selected from tyrosine and tryptophan, and wherein said hole modification comprises replacing an original amino acid residue from the interface of the Fc region with an amino acid residue selected from serine, threonine, valine and alanine. In some embodiments, the first Fc domain comprises at least two modifications at positions selected from L351, F405 and Y407, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, K392 and T394, per EU numbering. In some embodiments, the first Fc domain comprises at least two modifications at positions selected from Q347, Y349, T350, K370, G371, D399 and S400, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T350, S354, E357, K360, Q362E, S364, N390, K409 and T411, per EU numbering. In some embodiments, the first Fc domain comprises at least one substitution at positions selected from S354 and T366, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, L368 and Y407, per EU numbering. In some embodiments, the first Fc domain comprises at least one substitution selected from S354 and T366W, per EU numbering, and the second Fc domain comprises at least one substitution selected from T366S. L368A, Y407T, and Y407V, per EU numbering. In some embodiments, said constant region comprises at least one amino acid modifications, wherein said at least one amino acid modification increases binding affinity of saidconstant region for a neonatal fragment crystallizable receptor (FcRn) in acidic pH condition relative to said binding affinity of corresponding constant region prior to the at least one amino acid modification, and wherein a binding affinity of said constant region for said FcRn in neutral pH condition remains within 20% of corresponding binding affinity of said corresponding constant region prior to the at least one modification. In some embodiments, said binding affinity of said constant region for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in acidic pH condition relative to the corresponding constant region prior to the at least one modification. In some embodiments, said at least one modification decreases plasma clearance (CL), increases plasma retention time, or increases plasma half-life (t'A) relative to a corresponding IgG antibody construct prior to said at least one modification in said constant region. In some embodiments, a binding affinity of said constant region for a FcRn is increased in neutral pH condition relative to said binding affinity of a corresponding constant region prior to said at least one modification, and wherein a binding affinity of said constant region for said FcRn in acidic pH condition remains within 20% of said binding affinity of corresponding constant region prior to said at least one modification. In some embodiments, said binding affinity of said constant region for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in neutral pH condition relative to said binding affinity of corresponding constant region prior to the at least one modification. In some embodiments, the at least one modification increases plasma clearance of TL1A by the IgG antibody construct, compared to a corresponding plasma clearance by an IgG antibody construct prior to the at least one modification in the constant region. In some embodiments, the IgG antibody construct is an antibody, a Fab2 antibody, a bis-scFv antibody, a diabody, a DVD-Ig, a TandAb, a tandem scFv-Fc, a one-armed tandem scFv-Fc, a DART, a DART-Fc, or a functional fragment thereof. In some embodiments, the IgG antibody construct is an antibody, a variant thereof, or a functional fragment thereof. In some embodiments, the IgG antibody constructs further comprise a constant region, wherein said constant region comprises a first Fc domain and / or a second Fc domain. In some embodiments, said first Fc domain and said second Fc domain are derived from IgGl, IgG2, IgG3 or IgG4. In some embodiments, said first Fc domain and said second Fc domain are derived from IgGl constant domain. In some embodiments, said first Fc domain and said second Fc domain independently comprise M252Y, S254T, and T256E substitutions. In some embodiments, said first Fc domain and said second Fc domain independently comprise L234A and L235A substitutions. In some embodiments, said first Fc domain and said second Fc domain independently comprise P329G substitution. In some embodiments, said first Fc domain comprises a knob modification and said second Fc domain comprises a hole modification, wherein: said knob modification comprises replacing an original amino acid residue from an interface of the Fc region with an amino acid residue selected from tyrosine and tryptophan, and wherein said hole modification comprises replacing an original amino acid residue from the interface of the Fc region with an amino acid residue selected from serine, threonine, valine and alanine. In some embodiments, the first Fcdomain comprises at least two modifications at positions selected from L351, F405 and Y407, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, K392 and T394, per EU numbering. In some embodiments, the first Fc domain comprises at least two modifications at positions selected from Q347, Y349, T350, K370, G371, D399 and S400, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T350, S354, E357, K360, Q362E, S364, N390, K409 and T411, per EU numbering. In some embodiments, the first Fc domain comprises at least one substitution at positions selected from S354 and T366, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, L368 and Y407, per EU numbering. In some embodiments, the first Fc domain comprises at least one substitution selected from S354 and T366W, per EU numbering, and the second Fc domain comprises at least one substitution selected from T366S. L368A, Y407T, and Y407V, per EU numbering. In some embodiments, said constant region comprises at least one amino acid modifications, wherein said at least one amino acid modification increases binding affinity of said constant region for a neonatal fragment crystallizable receptor (FcRn) in acidic pH condition relative to said binding affinity of corresponding constant region prior to the at least one amino acid modification, and wherein a binding affinity of said constant region for said FcRn in neutral pH condition remains within 20% of corresponding binding affinity of said corresponding constant region prior to the at least one modification. In some embodiments, said binding affinity of said constant region for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in acidic pH condition relative to the corresponding constant region prior to the at least one modification. In some embodiments, said at least one modification decreases plasma clearance (CL), increases plasma retention time, or increases plasma half-life (t'A) relative to a corresponding IgG antibody construct prior to said at least one modification in said constant region. In some embodiments, a binding affinity of said constant region for a FcRn is increased in neutral pH condition relative to said binding affinity of a corresponding constant region prior to said at least one modification, and wherein a binding affinity of said constant region for said FcRn in acidic pH condition remains within 20% of said binding affinity of corresponding constant region prior to said at least one modification. In some embodiments, said binding affinity of said constant region for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in neutral pH condition relative to said binding affinity of corresponding constant region prior to the at least one modification. In some embodiments, the at least one modification increases plasma clearance of TL1A by the IgG antibody construct, compared to a corresponding plasma clearance by an IgG antibody construct prior to the at least one modification in the constant region.

[0013] Also provided herein are antibody constructs comprising a TL1A binding region that binds an epitope on TL1A, a variant thereof or a functional fragment thereof, wherein the TL1A binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises atleast one modification at positions selected from S30, T69, L83, N84, T104 and F107, relative to the amino acid position numbering of SEQ ID NO: 923. In some embodiments, the heavy chain variable region comprises at least one modification comprises a substitution selected from the group consisting of S30T, T69I, L83V, N84K, T104D, F107N and F107D, relative to the amino acid position numbering of SEQ ID NO: 923. In some embodiments, the at least one modification improves binding interaction with H109, Hl 18 and / or H121 of TL1A comprising an amino acid sequencer of SEQ ID NO: 139.

[0014] Also provided herein are antibody constructs comprising an IL-23 binding region that binds an epitope on IL-23, a variant thereof or a functional fragment thereof, wherein the IL-23 binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises at least one modification at positions selected from T28, T30, 131, A33, 134, G56, G58, H59, Q62, Q65, R98, E101, N102 and L108 relative to the amino acid position numbering of SEQ ID NO: 1544. In some embodiments, heavy chain variable region comprises at least one modification comprises a substitution selected from the group consisting of T28V, T28A, T28L, T28P, T30S, 13 IQ, A33T, I34M, I34V, G56K, G56A, G56N, G58A, H59Y, H59V, Q62S, Q62K, Q65R, Q65K, Q65A, R98I, E101S, EI0IY, E101T, N102F, N102Y, N102S, N102D, N102K, N102R, L108T and L108M relative to the amino acid position numbering of SEQ ID NO: 1544.

[0015] Also provided herein are pharmaceutical compositions comprising the IgG antibody construct described herein, or the antibody construct described herein, and a pharmaceutically acceptable carrier.

[0016] Also described herein are methods of treating a disease or a condition, wherein the method comprises administering an effective amount of the IgG antibody construct described herein, the antibody construct described herein, or the pharmaceutical composition of claim 109 to a subject in need thereof results in treatment of a disease or condition. In some embodiments, the disease or condition is related to impaired mitochondrial dysfunction. In some embodiments, the disease or condition is selected from the group consisting of: rheumatoid arthritis, Crohn's Disease (CD), ulcerative colitis (UC), psoriatic arthritis, ankylosing spondylitis, psoriasis, primary biliary cirrhosis, systemic lupus erythematosus or combinations thereof.INCORPORATION BY REFERENCE

[0017] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE FIGURES

[0018] The features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0019] FIG. 1A-1F depict a bispecific antibody comprising two binding domains. Specifically, FIG. 1A depicts a bispecific antibody having TL1A binding domain and IL-6R binding domain. FIG. IB depicts a bispecific antibody having a Fab domain and an scFv domain, wherein the Fab domain is a TL1A binding domain and the scFv domain is an IL-17 family cytokine binding domain. FIG. 1C depicts a bispecific antibody is Fab2 having two Fab domains, wherein the first Fab domain is a TL1A binding domain and the second Fab domain is an IL-17R binding domain. FIG. ID depicts a bispecific antibody having TL1A binding domain and IL-12 binding domain. FIG. IE depicts a bispecific antibody having a Fab domain and an scFv domain, wherein the Fab domain is a TL1A binding domain and the scFv domain is an IL-23 binding domain. FIG. IF depicts a bispecific antibody is Fab2 having two Fab domains, wherein the first Fab domain is a TL1A binding domain, and the second Fab domain is an IL-6 binding domain.

[0020] FIGS. 2A-2B show representative results of competitive binding assay for TL1A binding antibody candidates. FIG. 2A shows the competitive binding assay result for TL1A binding antibody candidate 1 having a VH amino acid sequence of SEQ ID NO: 923, and a VL amino acid sequence of SEQ ID NO: 1768. FIG. 2B shows the competitive binding assay result for TL1A binding antibody candidate 2 having a VH amino acid sequence of SEQ ID NO: 1048, and a VL amino acid sequence of SEQ ID NO: 1768.

[0021] FIGS. 3A-3B show representative results of competitive binding assay for IL-23 binding antibody candidates. FIG. 3A shows the competitive binding assay result for IL-23 binding antibody candidate 1 having a VH amino acid sequence of SEQ ID NO: 1544, and a VL amino acid sequence of SEQ ID NO: 1768. FIG. 3B shows the competitive binding assay result for IL-23 binding antibody candidate 2 having a VH amino acid sequence of SEQ ID NO: 1621, and a VL amino acid sequence of SEQ ID NO: 1768.

[0022] FIG. 4 summarize results blocking effect of TL1A binding region of multispecific antibodies prepared by fab-arm exchange method using luciferase assay. Luciferase assay was conducted at 130.0 ng / mL concentration of TL1A with each of five antibodies at a concentration ranging from 0.1, 1.0 or 10 pg / mL. The five antibodies included (1) monomeric IL-23 binding antibody comprising a VH amino acid sequence of SEQ ID NO: 375 and aVL amino acid sequence of SEQ ID NO: 463, (2) heterodimeric IL-23 / IL-12 binding antibody comprising a VH amino acid sequence of SEQ ID NO: 283 and a VL amino acid sequence of SEQ ID NO: 303, (3) TL1A binding antibody comprising a VH amino acid sequence of SEQ ID NO: 487 and a VL sequence comprising an amino acid sequence of SEQ ID NO: 491, (4) bispecific antibody-1 comprising a first VH amino acid sequence of SEQ ID NO: 375, a first VL amino acid sequence of SEQ ID NO: 463, a second VH amino acid sequence of SEQ ID NO: 487 and a second VL sequence comprising an amino acid sequence of SEQ ID NO: 491, and (5) bispecific antibody-2 comprising a first VH amino acid sequence of SEQ ID NO: 283, a first VL amino acid sequence of SEQ ID NO:303, a second VH amino acid sequence of SEQ ID NO: 487 and a second VLsequence comprising an amino acid sequence of SEQ ID NO: 491. Each antibody candidate comprised hlgGl constant region with L234A, L235A, M252Y, S254T, T256E and P329G modifications. For negative and positive control, only cells and cells in combination with TL1A were used, respectively. Results of the assay are showed for the monomeric IL-23 binding antibody, heterodimeric IL-23 / IL-12 binding antibody, TL1A binding antibody, bispecific antibody- 1 and bispecific antibody-2 (from left to right).

[0023] FIG. 5 summarize results blocking effect of TL1A binding region of multispecific antibodies prepared by key-in-hole method using luciferase assay. Luciferase assay was conducted at 130.0 ng / mL concentration of TL1A with each of four antibodies at a concentration ranging from 0.1, 1.0 or 10 pg / mL. The four antibodies are described in TABLE 45 as bispecific antibody candidate II- 1 to II-4. For negative and positive control, only cells and cells in combination with TL1A were used, respectively. Results of the assay are showed for bispecific antibody candidate II- 1, bispecific antibody candidate II-2, bispecific antibody candidate II-3, and bispecific antibody candidate II -4 (from left to right).

[0024] FIGS. 6A-6C shows representative binding curves for three knob-in-hole antibody constructions prepared in Example 10. FIGS. 6A, 6B and 6C show bispecific antibody candidate II- 1, bispecific antibody candidate II-2, and bispecific antibody candidate II-3, respectively.

[0025] FIG. 7 summarize results blocking effect of IL-23 binding region of multispecific antibodies prepared by fab-arm exchange method using luciferase assay. Luciferase assay was conducted on cells treated with IL-23 and each of five antibodies at a concentration ranging from 0.1, 1.0 or 10 pg / mL. The five antibodies included (1) monomeric IL-23 binding antibody comprising a VH amino acid sequence of SEQ ID NO: 375 and a VL amino acid sequence of SEQ ID NO: 463, (2) heterodimeric IL-23 / IL-12 binding antibody comprising a VH amino acid sequence of SEQ ID NO: 283 and a VL amino acid sequence of SEQ ID NO: 303, (3) TL1A binding antibody comprising a VH amino acid sequence of SEQ ID NO: 487 and a VL sequence comprising an amino acid sequence of SEQ ID NO: 491, (4) bispecific antibody-1 comprising a first VH amino acid sequence of SEQ ID NO: 375, a first VL amino acid sequence of SEQ ID NO: 463, a second VH amino acid sequence of SEQ ID NO: 487 and a second VL sequence comprising an amino acid sequence of SEQ ID NO: 491, and (5) bispecific antibody-2 comprising a first VH amino acid sequence of SEQ ID NO: 283, a first VL amino acid sequence of SEQ ID NO:303, a second VH amino acid sequence of SEQ ID NO: 487 and a second VL sequence comprising an amino acid sequence of SEQ ID NO: 491. Each antibody candidate comprised hlgGl constant region with L234A, L235A, M252Y, S254T, T256E and P329G modifications. For negative and positive control, only cells and cells in combination with IL-23 were used, respectively. Results of the assay are showed for the monomeric IL-23 binding antibody, heterodimeric IL-23 / IL-12 binding antibody, TL1A binding antibody, bispecific antibody- 1 and bispecific antibody-2 (from left to right).

[0026] FIG. 8 summarize results blocking effect of IL-23 binding region of multispecific antibodies prepared by key-in-hole method using luciferase assay. Luciferase assay was conducted for IL-23 with each of four antibodies at a concentration ranging from 0.1, 1.0 or 10 pg / mL. The four antibodies are described in TABLE 45 as bispecific antibody candidate II- 1 to II-4. For negative and positive control, only cells and cells in combination with IL-23 were used, respectively. Results of the assay are showed for bispecific antibody candidate II- 1, bispecific antibody candidate II-2, bispecific antibody candidate II-3, and bispecific antibody candidate II -4 (from left to right).DETAILED DESCRIPTION OF EMBODIMENTS

[0027] The following description and examples illustrate embodiments of the present disclosure in detail. It is to be understood that this disclosure is not limited to the particular embodiments described herein and as such can vary. Those of skill in the art will recognize that there are numerous variations and modifications of this disclosure, which are encompassed within its scope.

[0028] All terms are intended to be understood as they would be understood by a person skilled in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains.

[0029] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0030] Although various features of the present disclosure may be described in the context of a single embodiment, the features can also be provided separately or in any suitable combination. Conversely, although the present disclosure may be described herein in the context of separate embodiments for clarity, the present disclosure can also be implemented in a single embodiment.Definitions

[0031] The following definitions supplement those in the art and are directed to the current application and are not to be imputed to any related or unrelated case, e.g., to any commonly owned patent or application. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present disclosure, the preferred materials and methods are described herein. Accordingly, the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0032] In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

[0033] Reference in the specification to “some embodiments,” “an embodiment,” “one embodiment” or “other embodiments” means that a particular feature, structure, or characteristic described inconnection with the embodiments is included in at least some embodiments, but not necessarily all embodiments, of the present disclosure.

[0034] As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or composition of the present disclosure, and vice versa. Furthermore, compositions of the present disclosure can be used to achieve methods of the present disclosure.

[0035] The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i. e. , the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. In another example, the amount “about 10” includes 10 and any amounts from 9 to 11. In yet another example, the term “about” in relation to a reference numerical value can also include a range of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value. Alternatively, particularly with respect to biological systems or processes, the term “about” can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term “about” meaning within an acceptable error range for the particular value should be assumed.

[0036] As used herein, the terms, “disease”, “disorder”, and “condition,” which are used interchangeably herein, refer to any alternation in state of the body or of some of the organs, interrupting or disturbing the performance of the functions and / or causing symptoms such as discomfort, dysfunction, distress, or even death to the person afflicted or those in contact with a person. A disease or disorder can also be related to a distemper, ailing, ailment, malady, disorder, sickness, illness, complaint, or affectation.

[0037] As used herein, the term, “in need thereof,” when used in the context of a therapeutic or prophylactic treatment, means having a disease, being diagnosed with a disease, or being in need of preventing a disease, e.g., for one at risk of developing the disease. Thus, a subject in need thereof can be a subject in need of treating or preventing a disease.

[0038] As used herein, the term, "administering," refers to the placement of a compound (e.g., an antibody or fragment thereof as disclosed herein) into a subject by a method or route that results in at least partial delivery of the agent at a desired site . Pharmaceutical compositions comprising an antibody or fragment thereof, disclosed herein can be administered by any appropriate route which results in aneffective treatment in the subject, including but not limited to intravenous, intraarterial, subcutaneous injection or infusion directly into a tissue parenchyma, etc. Where necessary or desired, administration can include, for example, intracerebroventricular (“icv”) administration, intranasal administration, intracranial administration, intracelial administration, intracerebellar administration, subcutaneous administration, or intrathecal administration.

[0039] As used herein, the term, "subject", “patient”, “individual” and like terms, which are used interchangeably, refer to a vertebrate, a mammal, a primate, or a human. Mammals include, without limitation, humans, primates, rodents, wild or domesticated animals, including feral animals, farm animals, sport animals, and pets. Primates include, for example, chimpanzees, cynomolgus monkeys, spider monkeys, and macaques (e.g., Rhesus). Rodents include, for example, mice, rats, woodchucks, ferrets, rabbits and hamsters. Domestic and game animals include, for example, cows, horses, pigs, deer, bison, buffalo, feline species (e.g., domestic cat), and canine species (e.g., dog, fox and wolf,) avian species (e.g., chicken, emu and ostrich), and fish (e.g., trout, catfish and salmon). The terms, “individual,” “patient” and “subject” are used interchangeably herein. A subject can be male or female. In some embodiments, the subject is a mammal. The mammal can be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but is not limited to these examples. Mammals other than humans can be advantageously used as subjects that represent animal models of conditions or disorders. Nonlimiting examples include murine models. In addition, the compositions and methods described herein can be used to treat domesticated animals and / or pets. A subject can be one who is diagnosed and currently being treated for, or seeking treatment, monitoring, adjustment or modification of an existing therapeutic treatment, or is at a risk of developing a given disorder.

[0040] As used herein, the terms, “protein", “peptide” and “polypeptide," which are used interchangeably, refer to designate a series of amino acid residues connected to each other by peptide bonds between the alpha-amino and carboxy groups of adjacent residues. The terms "protein", “peptide” and "polypeptide" refer to a polymer of amino acids, including modified amino acids (e.g., phosphorylated, glycated, glycosylated, etc.) and amino acid analogs, regardless of its size or function. "Protein" and “polypeptide” are often used in reference to relatively large polypeptides, whereas the term "peptide" is often used in reference to small polypeptides, but usage of these terms in the art overlaps. The terms "protein", “peptide” and "polypeptide" are used interchangeably herein when referring to a gene product and fragments thereof. These terms encompass, e.g., native and artificial proteins, protein fragments and polypeptide analogs (such as muteins, variants, and fusion proteins) of a protein sequence as well as post-translationally, or otherwise covalently or non-covalently, modified proteins. A peptide, polypeptide, or protein may be monomeric or polymeric. A polypeptide can have the amino acid sequence of naturally occurring polypeptide from any mammal. Such native sequence polypeptide can be isolated from nature or can be produced by recombinant or synthetic means. In some embodiments, the polypeptide is a “variant”. “Variant” means a biologically active polypeptide having at least about 80% amino acid sequence identity with the native sequence polypeptide after aligning thesequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Such variants include, for instance, polypeptides wherein one or more amino acid residues are added, or deleted, at the N- or C-terminus of the polypeptide. In some embodiments, a variant will have at least about 80% amino acid sequence identity. In some embodiments, a variant will have at least about 90% amino acid sequence identity. In some embodiments, a variant will have at least about 95% amino acid sequence identity with the native sequence polypeptide. A “derivative” of a polypeptide is a polypeptide (e.g., an antibody) that has been chemically modified, e.g. , via conjugation to another chemical moiety (such as, for example, polyethylene glycol or albumin, e.g., human serum albumin), phosphorylation, and glycosylation.

[0041] As used herein, the term, “percent identity,” in the context of two or more nucleic acid or polypeptide sequences, refer to two or more sequences or subsequences that have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned for maximum correspondence, as measured using one of the sequence comparison algorithms described below (e.g., using publicly available computer software such as BLAST, BLASTP, BLASTN, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, or MUSCLE software or other algorithms available to persons of skill) or by visual inspection. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (ncbi.nlm.nih.gov). Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. Depending on the application, the percent “identity” can exist over a region of the sequence being compared, e.g., over a functional domain, or, alternatively, exist over the full length of the two sequences to be compared. For sequence comparison, typically one sequence acts as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444 (1988), by computerized implementations ofthese algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (see generally Ausubel et al., infra).

[0042] As used herein, the terms, “increased” / ‘increase”, and “enhance,” refer to an increase by a statistically significant amount; for the avoidance of doubt, the terms “increased”, “increase”, or “enhance”, mean an increase of at least 10% as compared to a reference level, for example an increaseof at least about 10%, at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3 -fold, or at least about a 4-fold, or at least about a 5 -fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level.

[0043] As used herein, the term “antibody” refers to an immunoglobulin molecule that specifically binds to, or is immunologically reactive toward, a specific target which in the current instance can be, for example, TL1A, IL-6R, IL-6, IL-12, IL-23, IL-12p35, IL-12p40, IL-23pl9, an IL-17 family cytokine, IL-17R, a variant thereof, or fragments thereof. Antibody can include, for example, polyclonal, monoclonal, genetically engineered, and fragments thereof. An antibody can be, for example, murine, chimeric, humanized, heteroconjugate, bispecific, diabody, triabody, or tetrabody. The fragment can include, for example, Fab’, F(ab’)2 , Fab, Fv, rlgG, scFv, hcAbs (heavy chain antibodies), a single domain antibody, VHH, VNAR , sdAbs, or nanobody. The term “monoclonal antibodies,” as used herein, refers to antibodies that are produced by a single clone of B-cells and bind to the same epitope. In contrast, “polyclonal antibodies” refer to a population of antibodies that are produced by different B-cells and bind to different epitopes of the same target. A whole antibody may comprise four polypeptides: two identical copies of a heavy (H) chain polypeptide and two identical copies of a light (L) chain polypeptide. Each of the heavy chains may contain one N-terminal variable (VH) region and three C-terminal constant (CHI, CH2 and CH3) regions, and each light chain may contain one N-terminal variable (VL) region and one C-terminal constant (CL) region. The variable regions of each pair of light and heavy chains may form a binding site of an antibody. In exemplary embodiments of bispecific antibodies, multiple distinct binding sites may be present. The VH and VL regions may have a similar general structure, with each region comprising four framework regions, whose sequences are relatively conserved. In some embodiments, the framework regions may be connected by three complementarity determining regions (CDRs). In some embodiments, the three CDRs, known as CDR1, CDR2, and CDR3, form the “hypervariable region” of an antibody, which is responsible for binding.

[0044] As used herein, the term, “chimeric antibody,” refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0045] As used herein, the term, “human antibody,” refers to an antibody comprising an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody-encoding sequences (e.g., obtained from human sources or designed de novo).

[0046] As used herein, the term, “humanized antibody,” refers to an amino acid sequence that differsfrom the amino acid sequence of an antibody derived from a non-human species by one or more amino acid substitutions, deletions, and / or additions, such that the humanized antibody is less likely to induce an immune response, and / or induces a less severe immune response, as compared to the non-human species antibody, when it is administered to a human subject. In some embodiments, certain amino acids in the framework and constant domains of the heavy and / or light chains of the non-human species antibody are mutated to produce the humanized antibody. In some embodiments, the constant domain(s) from a human antibody are fused to the variable domain(s) of a non-human species. In another embodiment, one or more amino acid residues in one or more CDR sequences of a non-human antibody are changed to reduce the likely immunogenicity of the non-human antibody when it is administered to a human subject, wherein the changed amino acid residues either are not critical for immunospecific binding of the antibody to its target, or the changes to the amino acid sequence that are made are conservative changes, such that the binding of the humanized antibody to the target is not significantly worse than the binding of the non-human antibody to the target. Examples of how to make humanized antibodies can be found in U.S. Pat. Nos. 6,054,297, 5,886,152 and 5,877,293. For further details, see Jones et al., Nature, 1986, 321:522-525; Riechmann et al., Nature, 1988, 332:323-329; and Presta, Curr. Op. Struct. Biol., 1992, 2:593-596, each of which is incorporated by reference in its entirety.

[0047] As used herein, the term, “epitope,” means a portion of a target that specifically binds to an antibody. Epitopes frequently consist of surface-accessible amino acid residues and / or sugar side chains and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter may be lost in the presence of denaturing solvents. An epitope may comprise amino acid residues that are directly involved in the binding, and other amino acid residues, which are not directly involved in the binding. The epitope to which an antibody binds can be determined using known techniques for epitope determination such as, for example, testing for antibody binding to TL1A, a variant thereof or a fragment thereof; any one of IL-6, IL-6R, IL-12, IL-23, IL- 12p35, IL-12p40, IL-23pl9, an IL-17 family cytokine, IL-17R, a variant thereof or a fragment thereof; or a combination thereof.

[0048] As used herein, the term, "Complementarity Determining Regions" (CDRs, z.e., CDR1, CDR2, and CDR3), refers to the amino acid residues of an antibody variable domain the presence of which are necessary for binding. Each variable domain typically has three CDR regions identified as CDR1, CDR2 and CDR3. The CDRs of variable heavy chain can be CDR-H1, CDR-H2 and CDR-H3. The CDRs of variable light chain can be CDR-L1, CDR-L2 and CDR-L3. Exemplary hypervariable loops occur at amino acid residues 26-32 (LI), 50-52 (L2), 91-96 (L3), 26-32 (Hl), 53-55 (H2), and 96-101 (H3). Exemplary CDRs (CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3) occur at amino acid residues 24-34 of LI, 50-56 of L2, 89-97 of L3, 31-35B of Hl, 50-65 ofH2, and 95-102 of H3. Thus, the HVs may be comprised within the corresponding CDRs and references herein to the"hypervariable loops" of VH and VL domains should be interpreted as also encompassing the corresponding CDRs, and vice versa, unless otherwise indicated. The more highly conserved regions of variable domains are called the framework region (FR), as defined below. The variable domains of native heavy and light chains each comprise four FRs (FR1, FR2, FR3 and FR4, respectively), largely adopting a [beta] -sheet configuration, connected by the three hypervariable loops. The hypervariable loops in each chain are held together in close proximity by the FRs and, with the hypervariable loops from the other chain, contribute to the formation of the binding site of antibodies. Structural analysis of antibodies revealed the relationship between the sequence and the shape of the binding site formed by the complementarity determining regions. Despite their high sequence variability, five of the six loops adopt just a small repertoire of main -chain conformations, called "canonical structures". These conformations are first of all determined by the length of the loops and secondly by the presence of key residues at certain positions in the loops and in the framework regions that determine the conformation through their packing, hydrogen bonding or the ability to assume unusual main-chain conformations. The antibodies or fragment thereof of the present disclosure can comprise a CDR3 region that is a length ofat least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acids in length. The antibodies or fragment thereof of the present disclosure can comprise a CDR3 region that is at least about 18 amino acids in length.

[0049] As used herein, the term, “variable region,” when used in reference to an antibody, refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. The variable regions of the heavy and light chain each consist of four framework regions (FR) connected by three complementarity determining regions (CDRs) also known as hypervariable regions. The CDRs in each chain are held together in close proximity by the FRs and, with the CDRs from the other chain, contribute to the formation of the target-binding site of antibodies. There are at least two techniques for determining CDRs: (1) an approach based on cross-species sequence variability; and (2) an approach based on crystallographic studies of target-antibody complexes. A CDR may refer to CDRs defined by either approach or by a combination of both approaches. Six hypervariable loops (three loops each from the Heavy and Light chain) contribute the amino acid residues for target-binding and confer target-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for a target) has the ability to recognize and bind target, although at a lower affinity than the entire binding site.

[0050] As used herein, the term, “constant region,” when used in reference to an antibody, refers to the constant region of the antibody light chain (j.e. , a light chain constant region) or the constant region of the antibody heavy chain (z.e., a heavy chain constant region) either alone or in combination. The constant region does not vary with respect to target specificity.

[0051] As used herein, the terms, "heavy chain region," includes amino acid sequences derived from the constant domains of an immunoglobulin heavy chain. A polypeptide comprising a heavy chainregion comprises at least one of: a CHI domain, a hinge (e.g. , upper, middle, and / or lower hinge region) domain, a CH2 domain, a CH3 domain, or a variant or fragment thereof. In an embodiment, an antibody or a fragment thereof may comprise the Fc region of an immunoglobulin heavy chain (e.g., a hinge portion, a CH2 domain, and a CH3 domain). In another embodiment, an antibody or a fragment thereof lacks at least a region of a constant domain (e.g., all or part of a CH2 domain). In some embodiments, at least one, and preferably all, of the constant domains are derived from a human immunoglobulin heavy chain. For example, in one preferred embodiment, the heavy chain region comprises a fully human hinge domain. In other preferred embodiments, the heavy chain region comprising a fully human Fc region (e.g., hinge, CH2 and CH3 domain sequences from a human immunoglobulin). In some embodiments, the constituent constant domains of the heavy chain region are from different immunoglobulin molecules.

[0052] As used herein, the term, "hinge region," includes the region of a heavy chain molecule that joins the CHI domain to the CH2 domain. The hinge region can comprise approximately 25 residues and is flexible, thus allowing the two N-terminal binding regions to move independently. Hinge regions can be subdivided into three distinct domains: upper, middle, and lower hinge domains.

[0053] As used herein, the term "Fv" is the minimum antibody fragment that contains a complete target-recognition and -binding site. This fragment consists of a dimer of one heavy- and one lightchain variable region domain in tight, non-covalent association. From the folding of these two domains emanate six hypervariable loops (three loops each from the H and L chain) that contribute the amino acid residues for binding and confer binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for a target) has the ability to recognize and bind target, although at a lower affinity than the entire binding site.

[0054] As used herein, the term, “heavy chain variable region” or “VH,” when used in reference to an antibody, refers to the fragment of the heavy chain that contains three CDRs interposed between flanking stretches known as framework regions, these framework regions are generally more highly conserved than the CDRs and form a scaffold to support the CDRs.

[0055] As used herein, the term, “light chain variable region” or “VL,” when used in reference to an antibody, refers to the fragment of the light heavy chain that contains three CDRs interposed between flanking stretches known as framework regions, these framework regions are generally more highly conserved than the CDRs and form a scaffold to support the CDRs.

[0056] As used herein, the term, “framework residues” or “FR,” are those variable domain amino acid residues other than the hypervariable region amino acid residues.

[0057] As used herein, the term, “antibody heavy chain,” refers to the larger of the two types of polypeptide chains present in antibody molecules in their naturally occurring conformations, and which normally determines the class to which the antibody belongs.

[0058] As used herein, the term, “antibody light chain,” refers to the smaller of the two types ofpolypeptide chains present in antibody molecules in their naturally occurring conformations. Kappa (“K”) and lambda (“X”) light chains refer to the two major antibody light chain isotypes.

[0059] As used herein, the phrase, “specifically binds” or “preferentially binds,” refers to an antibody or fragment thereof that binds to a target with greater affinity and / or avidity than it binds to epitopes on unrelated polypeptides. The specificity of an antibody or fragment thereof can be determined based on affinity and / or avidity. Methods to determine such specific binding are also well known in the art.

[0060] As used herein, the term, "binding affinity," refers to the strength of the sum total of noncovalent interactions between a first molecule and a second molecule. Unless indicated otherwise, the binding affinity refers to intrinsic binding affinity reflecting interaction between the first molecule and the second molecule at a ratio of 1 : 1.

[0061] As used herein, the term, “multispecific antibody,” is an antibody that comprises two or more different target-binding domains that collectively specifically bind two or more different epitopes. The two or more different epitopes may be epitopes on the same cell or on different cells. In some embodiments, a multi-specific antibody binds two different epitopes (z.e., a “bispecific antibody”). In some embodiments, a multi-specific antibody binds three different epitopes (z.e., a “trispecific antibody”).

[0062] As used herein a “recombinant antibody” is an antibody that comprises an amino acid sequence derived from two different species, or two different sources, and includes synthetic and / or non-naturally-occurring molecules. By way of non-limiting example, a recombinant antibody may comprise a non-human CDR and a human variable region framework or constant or Fc region, an antibody with binding domains from two different monoclonal antibodies, or an antibody comprising a mutation of one or more amino acid residues to increase or decrease biological activity or binding of a part of the antibody. In certain embodiments, recombinant antibodies are produced from a recombinant DNA molecule or synthesized. In certain embodiments, the antibodies described herein are a polypeptide(s) encoded by one or more polynucleotides.

[0063] As used herein, “recognize” or “bind” or “selective for” refers to the association or binding between a binding domain and a target domain.

[0064] As used herein, an “antibody construct” refers to a construct that may contain a binding domain and an Fc domain.

[0065] As used herein, a “binding domain” refers to an antibody or non-antibody domain.

[0066] As used herein, a “binding domain” refers to a domain from an antibody or from a nonantibody that can bind to a target domain. Binding domains can be numbered when there is more than one binding domains in a given conjugate or antibody construct (e.g., first binding domain, second binding domain, third binding domain, etc.). Different binding domains in the same conjugate or construct can target the same target or different targets.

[0067] As used herein, an “Fc domain” refers to an Fc domain from an antibody or from a nonantibody that can bind to an Fc receptor. As used herein, an “Fc domain” and an “Fc comprising domain” can be used interchangeably.

[0068] As used herein, a “target binding domain” refers to a construct that contains a binding domain from an antibody or from a non-antibody that can bind to a target (e.g. TL1A, IL-6, IL-6R, IL-12, IL- 23, IL-12p35, IL-I2p40, IL-23pl9, an IL-17 family cytokine, IL-17R).

[0069] As used herein, the abbreviations for the natural 1- enantiomeric amino acids are conventional and can be as follows: alanine (A, Ala); arginine (R, Arg); asparagine (N, Asn); aspartic acid (D, Asp); cysteine (C, Cys); glutamic acid (E, Glu); glutamine (Q, Gin); glycine (G, Gly); histidine (H, His); isoleucine (I, He); leucine (L, Leu); lysine (K, Lys); methionine (M, Met); phenylalanine (F, Phe); proline (P, Pro); serine (S, Ser); threonine (T, Thr); tryptophan (W, Trp); tyrosine (Y, Tyr); valine (V, Vai). Unless otherwise specified, X can indicate any amino acid.

[0070] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects for instance, human beings and animals, without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0071] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid fdler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0072] The terms “fragment of an antibody,” “antibody fragment,” “functional fragment of an antibody,” “binding domain” or their grammatical equivalents are used interchangeably herein to mean one or more fragments or portions of an antibody that retain the ability to specifically bind to a target. The antibody fragment desirably comprises, for example, one or more CDRs, the variable region (orportions thereof), the constant region (or portions thereof), or combinations thereof. Examples of antibody fragments include, but are not limited to, (i) a Fab fragment, which is a monovalent fragment that may comprise VL, VH, CL, and CHI domains; (ii) a F(ab’)2 fragment, which is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the stalk region; (iii) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (iv) a single chain Fv (scFv), which is a monovalent molecule consisting of the two domains of the Fv fragment ( / . e. , VL and VH) joined by a synthetic linker which enables the two domains to be synthesized as a single polypeptide chain; and (v) a diabody, which is a dimer of polypeptide chains, wherein each polypeptide chain may comprise a VH connected to a VL by a peptide linker that is too short to allow pairing between the VH and VL on the same polypeptide chain, thereby driving the pairing between the complementary domains on different VH-VL polypeptide chains to generate a dimeric molecule having two functional target binding sites. Antibody fragments are known in the art. Other antibody fragments can include variable fragments of heavy chain antibodies (VHH).

[0073] As used herein, the term, “Fab,” refers to a region of an antibody composed of one constant and one variable domain of each of the heavy and the light chains (monovalent target-binding fragment), but wherein the heavy chain is truncated such that it lacks the CH2 and CH3 domain (z.e., VH, CHI, VL, and CL), and may also lack some or all of the hinge region. It can be produced by digestion of a whole antibody with the enzyme papain. Fab may refer to this region in isolation, or this region in the context of a full-length antibody, immunoglobulin construct or Fab fusion protein. Fab can be obtained by treating a whole antibody with pepsin, followed by reduction, to yield a molecule consisting of an intact light chain and a portion of a heavy chain comprising a VH and a single constant domain. Two Fab' fragments are obtained per antibody treated in this manner.

[0074] As used herein, the term, "scFv,” refers to an antibody fragment comprising the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain. Generally, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains that enables the scFv to form the desired structure for target-binding.

[0075] The term, “conservative amino acid substitution” or “conservative mutation,” refers to the replacement of one amino acid by another amino acid with a common property. A functional way to define common properties between individual amino acids is to analyze the normalized frequencies of amino acid changes between corresponding proteins of homologous organisms. According to such analyses, groups of amino acids may be defined where amino acids within a group exchange preferentially with each other, and therefore resemble each other most in their impact on the overall protein structure. Examples of conservative mutations include amino acid substitutions of amino acids within the sub-groups above, for example, lysine for arginine and vice versa such that a positive charge may be maintained; glutamic acid for aspartic acid and vice versa such that a negative charge may be maintained; serine for threonine such that a free -OH can be maintained; and glutamine for asparaginesuch that a free -NH2can be maintained. Alternatively or additionally, the therapeutic agents can comprise the amino acid sequence of the reference protein with at least one non-conservative amino acid substitution.

[0076] The terms “non-conservative mutation” or “non-conservative amino acid substitution” involve amino acid substitutions between different groups, for example, lysine for tryptophan, or phenylalanine for serine, etc. In this case, it is preferable for the non-conservative amino acid substitution to not interfere with or inhibit the biological activity of the therapeutic agent. The non- conservative amino acid substitution may enhance the biological activity of the therapeutic agent, such that the biological activity of the therapeutic agent is increased as compared to the wild-type therapeutic agent.

[0077] A “multispecific antibody” is an antibody that can bind simultaneously to at least two targets that are of different structure, e.g., two different target, two different epitopes on the same target, or a hapten and / or an epitope. A “multivalent antibody” is an antibody that can bind simultaneously to at least two targets that are of the same or different structure. Valency indicates how many binding arms or sites the antibody has to a single target or epitope (z. e. , monovalent, bivalent, tri valent or multivalent). The multivalency of the antibody means that it can take advantage of multiple interactions in binding to a target, thus increasing the avidity of binding to the target. Specificity indicates how many targets or epitopes an antibody is able to bind (z'.e., monospecific, bispecific, trispecific, multispecific). Using these definitions, a natural antibody is bivalent because it has two binding arms but is monospecific because it binds to one epitope. Multispecific, multivalent antibodies are constructs that have more than one binding region of different specificity. For example, the bispecific antibody constructs disclosed herein have a first binding region and a second binding region, wherein the first and second binding regions are distinct.

[0078] A “bispecific antibody” is an antibody that can bind simultaneously to two targets which are of different structure. Bispecific antibodies (BsAbs) and bispecific antibody fragments (bsFab) may have at least one arm (or binding domain) that specifically binds to, for example, a first target, and at least one other arm (or binding domain) that specifically binds to a second target. At least one of the first and the second targets may be a target produced by or associated with a diseased cell, tissue, organ or pathogen. A variety of bispecific antibodies can be produced using molecular engineering.

[0079] As used herein, the term, “vector,” refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a self-replicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as “expression vectors.”

[0080] As used herein, the terms, “host cell,” “host cell line” and “host cell culture,” are interchangeable and refer to cells into which an exogenous nucleic acid has been introduced, and theprogeny of such cells. Host cells include “transformants” (or “transformed cells”) and “transfectants” (or “transfected cells”), which each include the primary transformed or transfected cell and progeny derived therefrom. Such progeny may not be completely identical in nucleic acid content to a parent cell, and may contain mutations.

[0081] A bispecific antibody construct, or a composition described herein, is said to be administered in a “therapeutically effective amount” if the amount administered is physiologically significant. An agent is physiologically significant if its presence results in a detectable change in the physiology of a recipient subject. In particular embodiments, a bispecific antibody construct disclosed herein is physiologically significant if its presence invokes a response or mitigates the signs and symptoms of an infectious or autoimmune disease state. A physiologically significant effect could also be the evocation of a humoral and / or cellular immune response in the recipient subject.

[0082] The term “linker” is used to denote polypeptides comprising two or more amino acid residues joined by peptide bonds and are used to link one or more binding portions or variable domains.

[0083] An "Fv" or "Fv fragment" may consist of only the light chain variable domain (VL) and heavy chain variable domain (VH) of a "single arm" of an immunoglobulin. Thus an "Fv" is the minimum antibody fragment which contains a complete target-recognition and binding site. A "two-chain" Fv fragment consists of a dimer of one heavy- and one light-chain variable domain in tight, non-covalent association. A single-chain Fv species (scFv) may include a VH and a VL domain of an immunoglobulin, with these domains being present in a single polypeptide chain in which they are covalently linked to each other by a linker peptide. Typically, in a scFv fragment the variable domains of the light and heavy chain associate in a dimeric structure analogous to that in a two-chain Fv species. In single chain Fv fragments, it is possible to either have the variable domain of the light chain arranged at the N-terminus of the single polypeptide chain, followed by the linker and the variable domain of the heavy chain arranged at the C-terminus of the polypeptide chain or vice versa, having the variable domain of the heavy chain arranged on the N-terminus and the variable domain of the light chain at the C-terminus with the linker peptide arranged in between. The linker peptide can be any flexible linker known in the art, for example, made from glycine and serine residues. It is also possible to additionally stabilize the domain association between the VH and the VL domain by introducing disulfide bonds into conserved framework regions. Such scFv fragments are also known as disulfide-stabilized scFv fragments (ds-scFv).

[0084] As used herein, the term, “treating” (and variations thereof such as “treat” or “treatment”), refers to clinical intervention in an attempt to alter the natural course of a disease or condition in a subject in need thereof. Treatment can be performed during the course of clinical pathology. Desirable effects of treatment include cure (if applicable), delay the onset of, reduce the severity of, alleviate, ameliorate one or more symptoms of the disease, improve the disease, reduce or improve any associated symptoms of the disease or the predisposition toward the development of the disease.

[0085] As used herein, the term, “sufficient amount,” means an amount sufficient to produce a desired effect, e.g., an amount sufficient to modulate an immune response in a subject.

[0086] As used herein, the terms, “modulate” and “modulation,” refer to reducing or inhibiting or, alternatively, activating or increasing, a recited variable.Antibody Fragments

[0087] Antibody fragments which recognize specific epitopes can be generated by known techniques. Antibody fragments are binding portions of an antibody, such as, for example, F(ab')2, Fab', F(ab)2, Fab, Fv, scFv and the like. F(ab')2 fragments can be produced by pepsin digestion of the antibody molecule and Fab' fragments can be generated by reducing disulfide bridges of the F(ab')2 fragments. Alternatively, Fab' expression libraries can be constructed to allow rapid and easy identification of monoclonal Fab' fragments with the desired specificity. F(ab)2 fragments may be generated by papain digestion of an antibody.

[0088] A single chain Fv molecule (scFv) may comprise a VL domain and a VH domain. The VL and VH domains associate to form a target binding site. These two domains may be further covalently linked by a peptide linker (L).

[0089] Techniques for producing single domain antibodies (DABs or VHH) are also known in the art, as disclosed for example in Cossins et al. (2006, Prot Express Purif 51:253-259), incorporated herein by reference. Single domain antibodies may be obtained, for example, from camels, alpacas or llamas by standard immunization techniques. The VHH may have potent target binding capacity and can interact with novel epitopes that are inaccessible to conventional VH-VL pairs. Alpaca serum IgG contains about 50% camelid heavy chain only IgG antibodies (HCAbs). Alpacas may be immunized with known targets, such as TNF-a, and VHHs can be isolated that bind to and neutralize the target. PCR primers that amplify virtually all alpaca VHH coding sequences have been identified and may be used to construct alpaca VHH phage display libraries, which can be used for antibody fragment isolation by standard biopanning techniques well known in the art. In certain embodiments, VHH antibody fragments may be utilized in the claimed compositions and methods.

[0090] An antibody fragment can be prepared by proteolytic hydrolysis of the full-length antibody or by expression in E. coli or another host of the DNA coding for the fragment. An antibody fragment can be obtained by pepsin or papain digestion of full-length antibodies by conventional methods.Multispecific molecules

[0091] Multispecific molecules are antibodies that are capable of binding at least two different targets. In some embodiments, the at least two different targets comprise two different epitopes. In some embodiments, the two different epitopes are TL1A, a variant thereof or a functional fragment thereof, and a protein from any one of IL-6R, IL-6, IL-12, IL-23, IL-12p35, IL-12p40, IL-23pl9, an IL-17family cytokine, IL-17R, a variant thereof, and a functional fragment thereof. Multispecific molecules described herein may be considered multispecific antibodies.

[0092] Methods for making multispecific antibodies are known in the art. Traditionally, the recombinant production of multispecific antibodies is based on the co-expression of two immunoglobulin heavy-chain / light-chain pairs, where the two heavy chains have different specificities. The purification of the correct molecule is usually accomplished by affinity chromatography steps.

[0093] There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, 5, a, y, and p, respectively. Accordingly, multispecific antibodies described herein comprise kappa constant region, lambda constant region, alpha constant region, gamma constant region, delta constant region, epsilon constant region, mu constant region, a functional fragment thereof, or a combination thereof.

[0094] A class of antibody or immunoglobulin refers to the type of constant domain or constant region possessed by its heavy chain. In some embodiment, the heavy chain is an IgA. In some embodiment, the heavy chain is an IgD. In some embodiment, the heavy chain is an IgE. In some embodiment, the heavy chain is an IgG. In some embodiment, the heavy chain is an IgM. In some embodiment, the heavy chain is an IgGl. In some embodiment, the heavy chain is an IgG2. In some embodiment, the heavy chain is an IgG3. In some embodiment, the heavy chain is an IgG4. In some embodiment, the heavy chain is an IgAl. In some embodiment, the heavy chain is an IgA2.

[0095] In some embodiments, an antibody is an IgGl antibody. In some embodiments, an antibody is an IgG3 antibody. In some embodiments, an antibody is an IgG2 antibody. In some embodiments, an antibody is an IgG4 antibody. In some embodiments, an antibody is an IgAl antibody. In some embodiments, an antibody is an IgA2 antibody.

[0096] In some embodiments, a multispecific antibody described herein comprise two heavy chains, wherein each heavy chain binds nonidentical epitopes. Each heavy chain can have at one end a variable domain (VH) followed by a number of constant domains (three or four constant domains, CHI, CH2, CH3 and CH4, depending on the antibody class). In some embodiments, multispecific antibodies described herein comprise one or more light chains. Each light chain can have a variable domain (VL) at one end and a constant domain (CL) at its other end; the constant domain of the light chain is aligned with the first constant domain (CHI) of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain. In some embodiments, the light chains comprise kappa light chain or lambda light chain. Multispecific antibodies such as kappa or lambda antibodies can be made using any of a variety of art-recognized techniques, including those disclosed in WO 2012 / 023053, the contents of which are hereby incorporated by reference in their entirety.

[0097] In some embodiments, antibody variable domains with the desired binding specificities can be linked to immunoglobulin constant domain sequences to form multispecific antibodies. In some embodiments, the fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. In some embodiments, it is preferred to have the first heavy-chain constant region (CHI) containing the site necessary for light-chain binding present in at least one of the fusions. DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain, may be inserted into separate expression vectors, and may be co-transfected into a suitable host organism.

[0098] In some embodiments, the interface between a pair of antibody molecules in constructs herein is engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains to form a protuberance or knob (e.g., tyrosine or tryptophan). Compensatory cavities or holes of identical or similar size to the large side chain(s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g., serine, threonine, valine or alanine). This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as homodimers.

[0099] Techniques for generating bispecific antibodies from antibody functional fragments have been described in the literature. For example, bispecific antibodies can be prepared using chemical linkage. The bispecific antibodies can be used as agents for the selective immobilization of enzymes.

[0100] Various techniques for making and isolating bispecific antibody functional fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers. The leucine zipper peptides from the Fos and Jun proteins were linked to the Fab' portions of two different antibodies by gene fusion. The antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers. This method can also be utilized for the production of antibody homodimers. The “diabody” technology provides an alternative mechanism for making bispecific antibody functional fragments. The functional fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) by a linker which is too short to allow pairing between the two domains on the same chain. Accordingly, the VH and VL domains of one functional fragment are forced to pair with the complementary VL and VH domains of another functional fragment, thereby forming two targetbinding sites. Another strategy for making bispecific antibody functional fragments includes use of single-chain Fv (sFv) dimers.

[0101] Antibodies with more than two valences are contemplated. For example, trispecific antibodies can be prepared. Exemplary bispecific antibodies can bind to two different epitopes, at least one of which originates in the target described herein. Alternatively, an anti-target arm of an immunoglobulin molecule can be combined with an arm which binds to a triggering molecule on aleukocyte such as a T-cell receptor molecule (e.g., CD2, CD3, CD28, or B7), or Fc receptors for IgG (FcyR), such as FcyRI (CD64), FcyRII (CD32) and FcyRIII (CD 16) so as to focus cellular defense mechanisms to the cell expressing the particular protein. Bispecific antibodies can also be used to direct cytotoxic agents to cells which express a particular protein. These antibodies may possess a targetbinding arm and an arm which binds a cytotoxic agent or a radionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA. Another bispecific antibody of interest binds the target described herein and further binds tissue factor (TF).

[0102] Several strategies have been used to generate such multispecific molecules (e.g., bispecific molecules, trispecific molecules) such as chemical cross-linking of antibody functional fragments, forced heterodimerization, quadroma technology, fusion of antibody functional fragments via polypeptide linkers and use of single domain antibodies. The availability of recombinant DNA technologies has led to the generation of a multitude of bispecific antibody formats. Linkers and mutations have frequently been introduced into different regions of the antibody to force heterodimer formation or to connect different binding moieties into a single molecule.

[0103] In some embodiments, a multispecific antibody (e.g., bispecific antibody, trispecific antibody) comprises a first binding domain and a second binding domain, wherein the first binding domain binds a first target of TL1A, a variant thereof or a functional fragment thereof, and wherein a second binding domain binds a second target selected from IL-6R, IL-6, IL- 12, IL-23, IL-23pl9, IL-12p40, IL-12p35, an IL-17 family cytokine, IL-17R, a variant thereof and a functional fragment thereof. In some embodiments, a first binding domain comprises a first heavy chain variable region. In some embodiments, multispecific antibodies described herein comprise a first binding region, wherein the first binding region comprises a first heavy chain variable region and, optionally, a first light chain variable region. In some embodiments, a second binding domain comprises a second heavy chain variable region. In some embodiments, multispecific antibodies described herein comprise a second binding region, wherein the second binding region comprises a second heavy chain variable region and, optionally, a second light chain variable region. In some embodiments, the first heavy chain variable region and the first light chain variable region can bind the first target (TL1A, a variant thereof or a functional fragment thereof). In some embodiments, the second heavy chain variable region and the second light chain variable region can bind the second target (IL-6R, IL-6, IL-12, IL-23, IL-23pl9, IL- 12p40, IL-12p35, an IL-17 family cytokine, IL-17R, a variant thereof or a functional fragment thereof). In some embodiments, each of the first and second heavy chain variable regions comprises CDR-H1, CDR-H2, and CDR-H3. In some embodiments, each of the first and second light chain variable regions comprise CDR-L1, CDR-L2, and CDR-L3. In some embodiments, each of the first heavy chain variable region, the first light chain variable region, the second heavy chain variable region and the second light chain variable region comprise four framework regions. In some embodiments, at least one of the two heavy chain variable regions comprises a constant region (Fc). In some embodiments, at least one binding domain / binding region of a multispecific antibody comprises at least one modification thatchanges isoelectric point (pl) of the multispecific antibody. In some embodiments, the at least one modification in the variable region is within CDR-H1, CDR-H2, CDR-H3, at least one of framework regions of a heavy chain variable region, CDR-L1, CDR-L2, CDR-L3, at least one of framework regions of a light chain variable region, or combinations thereof. In some embodiments, the at least one modification in the variable region increases binding affinity of the multispecific antibody for at least one of the first and second target in neutral pH relative to binding affinity of a corresponding multispecific antibody prior to the at least one modification. In some embodiments, the at least one modification increases binding affinity of the multispecific antibody for at least one of the first and second target in neutral pH by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to binding affinity of a corresponding multispecific antibody prior to the at least one modification. Alternatively, in some embodiments, the at least one modification in CDR-H1, CDR-H2, CDR-H3, at least one of framework regions of a heavy chain variable region, CDR-L1, CDR-L2, CDR-L3, at least one of framework regions of a light chain variable region, or a combination thereof increases binding affinity of the multispecific antibody for at least one of the first and second target in neutral pH by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to binding affinity of a corresponding multispecific antibody prior to the at least one modification. In some embodiments, a binding affinity of the multispecific antibody comprising the at least one modification in the variable region for at least one of the first and second target in acidic pH remains within 5%, 10%, 15%, 20%, 25%, 30%, or 50% relative to binding affinity of a corresponding multispecific antibody prior to the at least one modification. Alternatively, in some embodiments, a binding affinity of the multispecific antibody comprising the at least one modification in CDR-H1, CDR-H2, CDR-H3, at least one of framework regions of a heavy chain variable region, CDR-L1, CDR-L2, CDR-L3, at least one of framework regions of a light chain variable region, or a combination thereof for at least one of the first and second target in acidic pH remains within 5%, 10%, 15%, 20%, 25%, 30%, or 50% relative to binding affinity of a corresponding multispecific antibody prior to the at least one modification. In some embodiments, the at least one modification in the variable region decreases binding affinity of the multispecific antibody for at least one of the first and second target in acidic pH by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to binding affinity of a corresponding multispecific antibody prior to the at least one modification. Alternatively, in some embodiments, the at least one modification in CDR-H1, CDR-H2, CDR-H3, at least one of framework regions of a heavy chain variable region, CDR-L1, CDR-L2, CDR-L3, at least one of framework regions of a light chain variable region, or a combination thereof decreases binding affinity of the multispecific antibody for at least one of the first and second target in acidic pH by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to binding affinity of a corresponding multispecific antibody prior to the at least one modification. In some embodiments, the at least one modification in a first heavy chain variable region and / or a first lightchain variable region increases binding interaction with histidine rich binding pocket of TL1A, a variant thereof, or a functional fragment thereof. Likewise, in some embodiments, the at least one modification in a second heavy chain variable region and / or a second light chain variable region increases binding interaction with histidine rich binding pocket of IL-6R, IL-6, IL-12, IL-23, IL-23pl9, IL-12p40, IL- 12p35, an IL-17 family cytokine, IL-17R, a variant thereof or a functional fragment thereof.

[0104] In some embodiments, multispecific antibody described herein comprise at least one constant region. In some embodiments, a constant region comprises at least one modification. In some embodiments, the at least one modification increases binding affinity of the constant region for a neonatal fragment crystallizable receptor (FcRn) in acidic pH relative to binding affinity of a corresponding constant region prior to the at least one modification. In some embodiments, a binding affinity of the constant region comprising the at least one modification for FcRn is increased in acidic pH by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more relative to binding affinity of a corresponding constant region prior to the at least one modification. In some embodiments, a binding affinity of the constant region comprising at least one modification for FcRn remains within remains within 5%, 10%, 15%, 20%, 25%, 30%, or 50% relative to binding affinity of a corresponding constant region prior to the at least one modification.

[0105] Alternatively, in some embodiments, at least one modification in a constant region increases binding affinity of the constant region for a neonatal fragment crystallizable receptor (FcRn) in neutral pH relative to binding affinity of a corresponding constant region prior to the at least one modification. Accordingly, in some embodiments, a binding affinity of the constant region comprising at least one modification is increased in neutral pH for FcRn by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more relative to binding affinity of a corresponding constant region prior to the at least one modification. In some embodiments, a binding affinity of the constant region comprising at least one modification for FcRn in acidic pH remains within 5%, 10%, 15%, 20%, 25%, 30%, or 50% relative to binding affinity of a corresponding constant region prior to the at least one modification.

[0106] In some embodiments, the multispecific molecule (e.g., bispecific molecules, trispecific molecules) comprises a mutant Fc domain. In some embodiments, the mutant Fc domain comprises one or more mutations. In some embodiments, the multispecific molecule comprising a mutant Fc domain has a longer half-life relative to the multispecific molecule comprising unmodified Fc domain. In some embodiments, the mutant Fc domain comprises one or more of M252Y, S254T, and T256E mutations relative to corresponding wildtype Fc domain, wherein the mutations extend half-life of the multispecific molecule. In some embodiments, the mutant Fc domain comprises one or more of M428L and N434S mutations relative to corresponding wildtype Fc domain, wherein the mutations extend half-life of the multispecific molecule. In some embodiments, the mutant Fc domain comprises one or more of T307A, E380A, and N434A mutations relative to corresponding wildtype Fc domain,wherein the mutations extend half-life of the multispecific molecule. In some embodiments, the mutant Fc domain comprises one or more of T250Q and M428L mutations relative to corresponding wildtype Fc domain, wherein the mutations extend half-life of the multispecific molecule. In some embodiments, the mutant Fc domain comprises one or more of T307Q, Q31 IV, and A378V mutations relative to corresponding wildtype Fc domain, wherein the mutations extend half-life of the multispecific molecule. In some embodiments, the mutant Fc domain comprises one or more of T256D, H286D, T307R, Q311V, and A378V mutations relative to corresponding wildtype Fc domain, wherein the mutations extend half-life of the multispecific molecule. In some embodiments, the mutant Fc domain comprises one or more of H285D, T307Q, and A378V mutations relative to corresponding wildtype Fc domain, wherein the mutations extend half-life of the multispecific molecule. In some embodiments, the mutant Fc domain comprises one or more of T256D, Q311V, and A378V mutations relative to corresponding wildtype Fc domain, wherein the mutations extend half-life of the multispecific molecule. In some embodiments, the mutant Fc domain comprises one or more of H285N, T307Q, and N315D mutations relative to corresponding wildtype Fc domain, wherein the mutations extend half-life of the multispecific molecule. In some embodiments, the mutant Fc domain comprises one or more of L235A and G237A mutations relative to corresponding wildtype Fc domain, wherein the mutations extend half-life of the multispecific molecule.

[0107] In some embodiments, the multispecific molecule is used for subcutaneous administration. In some embodiments, a mutant Fc domain of the multispecific molecule comprises a deletion of a c- terminal lysine relative to corresponding wild-type Fc domain. In some embodiments, the deletion of the c-terminal lysine of the Fc domain improves subcutaneous bioavailability of the multispecific molecule. Accordingly, in some embodiments, subcutaneous administration of an effective amount of a composition comprising multispecific molecule to a subject in need thereof results in treatment of a disease or condition, wherein the multispecific molecule comprises a mutant Fc domain, wherein the mutant Fc domain comprises a deletion of a c-terminal lysine relative to corresponding wild-type Fc domain.IL-6R

[0108] IL-6 family proteins bind to Interleukin-6 receptor (IL-6R). The IL-6 family, as described herein, include Interleukin-6 cytokine (IL-6), Interleukin- 11 cytokine (IL- 11), a functional fragment thereof, a variant thereof, a multimeric form thereof or a combination thereof. In some embodiments, antibodies targeting IL-6R are used for treating rheumatoid arthritis, giant cell arthritis, systemic sclerosis - interstitial lung disease (SSc-ILD), juvenile idiopathic arthritis (JIA), cytokine release syndrome (CRS), corona virus disease (COVID-2019), polymyalgia rheumatica, neuromyelitis optica spectrum disorder (NMOSD), scleroderma-associated interstitial lung disease (SSc-ILD), or combinations thereof. Amino acid sequences of IL-6R is recited in TABLE 1.TABLE 1. Amino Acid Sequences of IL-6R

[0109] In some embodiments, multispecific molecules described herein bind to an amino acid sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequences recited in TABLE 1. In some embodiments, multispecific molecules described herein bind to an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 1.

[0110] In some embodiments, multispecific molecules described herein comprise at least one of CDR- Hs described in TABLE 2 or a variant thereof, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOs: 2-10. In some embodiments, multispecific molecules described herein comprise any one of CDR-H1 described in TABLE 2 or a variant thereof, any one of CDR-H2 described in TABLE 2 or a variant thereof, and any one of CDR-H3 described in TABLE 2 or a variant thereof, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 1. In some embodiments, multispecific molecules described herein comprise any one of combinations of CDR-Hs or variants thereof described in TABLE 2, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 1. In some embodiments, the CDR-H variant comprises at least one, at least two or at least three substitutions, deletions, additions or combination thereof relative to a corresponding parent CDR-H sequence described in TABLE 2. In some embodiments, the CDR-H or the variant thereof comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to a corresponding parent CDR-H sequence described in TABLE 2.TABLE 2. Exemplary CDR-H sequences of antibodies for binding to IL-6R[OHl] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the CDR-Hs described in TABLE 2, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodies described herein comprise at least one modification within any one of framework regions, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is IL-6R, a variant thereof or a functional fragment thereof. In some embodiments, the multispecific antibodies comprising the at least one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more increase in binding affinity for the target peptide in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pH condition relative to a corresponding binding affinity prior to the at least one modification.

[0112] In some embodiments, multispecific molecules described herein comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of VH sequences described in TABLE 3, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 1.TABLE 3. Exemplary VH sequence of antibodies for binding to IL-6R

[0113] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the VH sequences described in TABLE 3, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodies described herein comprise at least one modification within any one of framework regions, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is IL-6R, a variant thereof or a functional fragment thereof. In some embodiments, the multispecific antibodies comprising the at least one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more increase in binding affinity for the target peptide in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pH condition relative to a corresponding binding affinity prior to the at least one modification.

[0114] In some embodiments, multispecific molecules described herein comprise at least one of CDR- Ls described in TABLE 4 or a variant thereof, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identicalto SEQ ID NO: 1 In some embodiments, multispecific molecules described herein comprise any one of CDR-L 1 described in TABLE 4 or a variant thereof, any one of CDR-L2 described in TABLE 4 or a variant thereof, and any one of CDR-L3 described in TABLE 4 or a variant thereof, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 1. In some embodiments, multispecific molecules described herein comprise any one of combinations of CDR-Ls or variants thereof described in TABLE 4, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 1. In some embodiments, the CDR-L variant comprises at least one, at least two or at least three substitutions, deletions, additions or combination thereof relative to a corresponding parent CDR-L sequence described in TABLE 4. In some embodiments, the CDR-L or the variant thereof comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to a corresponding parent CDR-L sequence described in TABLE 4TABLE 4. Exemplary CDR-L sequences of antibodies for binding to IL-6R

[0115] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the CDR-Ls described in TABLE 4, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodies described herein comprise at least one modification within any one of framework regions, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is IL-6R, a variant thereof or a functional fragment thereof. In some embodiments, the multispecific antibodies comprising the at least one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more increase in binding affinity for the target peptide in neutral pH conditionrelative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pH condition relative to a corresponding binding affinity prior to the at least one modification.

[0116] In some embodiments, multispecific molecules described herein comprise a combination of CDRs, wherein the CDRs comprises a CDR-H1 or a variant thereof, a CDR-H2 or a variant thereof, a CDR-H3 or a variant thereof, a CDR-L 1 or a variant thereof, a CDR-L2 or a variant thereof, and a CDR- L3 or a variant thereof, and wherein the combination is according to any one of the combinations provided in TABLE 5.TABLE 5. Exemplary CDR sequences of antibodies for binding to IL-6R

[0117] In some embodiments, multispecific molecules described herein comprise an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of VL sequences described in TABLE 6, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 1.TABLE 6. Exemplary VL sequence of antibodies for binding to IL-6R

[0118] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the VL sequences described in TABLE 6, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodiesdescribed herein comprise at least one modification within any one of framework regions, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is IL-6R, a variant thereof or a functional fragment thereof. In some embodiments, the multispecific antibodies comprising the at least one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more increase in binding affinity for the target peptide in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, multispecific antibodies described herein comprise two light chain variable region that are at least 90%, at least 95%, at least 98% or 100% identical relative to each other.

[0119] In some embodiments, multispecific antibodies comprise an IL-6R binding region, wherein the IL-6R binding region comprises an IL-6R binding heavy chain variable domain and, optionally, an IL- 6R binding light chain variable domain. In some embodiments, multispecific antibodies described herein comprise a binding affinity for IL-6R, a variant thereof or a functional fragment thereof that is at least 10%, at least 20%, at least 30%, at least 50%, at least 80%, at least 100%, at least 200% or more higher under neutral pH condition relative to the binding affinity under acidic pH condition. In some embodiments, multispecific antibodies described herein comprise a ratio of binding affinities for IL- 6R, a variant thereof or a functional fragment under neutral pH condition and acidic pH condition is at least 1.1, 1.5, 2, 3, 5, 8, 10, 100 or more. In some embodiments, multispecific antibodies described herein comprise a binding affinity for IL-6R, a variant thereof or a functional fragment thereof that is at least 10%, at least 20%, at least 30%, at least 50%, at least 80%, at least 100%, at least 200% or more higher at about pH 7.4 relative to the binding affinity at about pH 5.8. In some embodiments, multispecific antibodies described herein comprise a ratio of binding affinities for IL-6R, a variant thereof or a functional fragment at about pH 7.4 and about pH 5.8 is at least 1.1, 1.5, 2, 3, 5, 8, 10, 100 or more.

[0120] In some embodiments, multispecific molecules described herein comprise: (a) a VH sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of amino acid sequences described in TABLE 3; and (b) a VL sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least90%, at least 95% or 100% identical to any one of amino acid sequences described in TABLE 6, wherein the multispecific molecule comprises the VH sequence and the VL sequence according to the combination described in TABLE 7.TABLE 7. Exemplary VH and VL sequences of antibodies for binding IL-6RIL-6

[0121] The IL-6 family, as described herein, include Interleukin-6 cytokine (IL-6), a functional fragment thereof, a variant thereof, a multimeric form thereof or a combination thereof. In some embodiments, antibodies targeting IL-6 are used for treating rheumatoid arthritis, giant cell arthritis, systemic sclerosis - interstitial lung disease (SSc-ILD), juvenile idiopathic arthritis (JIA), cytokine release syndrome (CRS), corona virus disease (COVID-2019), polymyalgia rheumatica, neuromyelitis optica spectrum disorder (NMOSD), scleroderma-associated interstitial lung disease (SSc-ILD), or combinations thereof. Amino acid sequences of IL-6 is recited in TABLE 8.TABLE 8. Amino Acid Sequences of IL-6

[0122] In some embodiments, multispecific molecules described herein bind to an amino acid sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequences recited in TABLE 8. In some embodiments, multispecific molecules described herein bind to an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 221.

[0123] In some embodiments, multispecific molecules described herein comprise at least one of CDR- Hs described in TABLE 9 or a variant thereof, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOs: 222-239. In some embodiments, multispecific molecules described herein comprise any one of CDR-H1 described in TABLE 9 or a variant thereof, any one of CDR-H2 described in TABLE 9 or a variant thereof, and any one of CDR-H3 described in TABLE 9 or a variant thereof,wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 221. In some embodiments, multispecific molecules described herein comprise any one of combinations of CDR-Hs or variants thereof described in TABLE 9, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 221. In some embodiments, the CDR-H variant comprises at least one, at least two or at least three substitutions, deletions, additions or combination thereof relative to a corresponding parent CDR-H sequence described in TABLE 9. In some embodiments, the CDR-H or the variant thereof comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to a corresponding parent CDR-H sequence described in TABLE 9.TABLE 9. Exemplary CDR-H sequences of antibodies for binding to IL-6

[0124] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the CDR-Hs described in TABLE 9, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodies described herein comprise at least one modification within any one of framework regions, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is IL-6, a functional fragment thereof, a variant thereof, a multimeric form thereof or a combination thereof. In some embodiments, the multispecific antibodies comprising the at least one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more increase in bindingaffinity for the target peptide in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pH condition relative to a corresponding binding affinity prior to the at least one modification.

[0125] In some embodiments, multispecific molecules described herein comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of VH sequences described in TABLE 10, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 221.TABLE 10. Exemplary VH sequence of antibodies for binding to IL-6

[0126] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the VH sequences described in TABLE 10, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodies described herein comprise at least one modification within any one of framework regions, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is IL-6, a functional fragment thereof, a variant thereof, a multimeric form thereof or a combination thereof. In some embodiments, the multispecific antibodies comprising the atleast one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more increase in binding affinity for the target peptide in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pH condition relative to a corresponding binding affinity prior to the at least one modification.

[0127] In some embodiments, multispecific molecules described herein comprise at least one of CDR- Ls described in TABLE 11 or a variant thereof, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 221. In some embodiments, multispecific molecules described herein comprise any one of CDR-L 1 described in TABLE 11 or a variant thereof, any one of CDR-L2 described in TABLE 11 or a variant thereof, and any one of CDR-L3 described in TABLE 11 or a variant thereof, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 221. In some embodiments, multispecific molecules described herein comprise any one of combinations of CDR-Ls or variants thereof described in TABLE 11, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 221. In some embodiments, the CDR-L variant comprises at least one, at least two or at least three substitutions, deletions, additions or combination thereof relative to a corresponding parent CDR-L sequence described in TABLE 11. In some embodiments, the CDR-L or the variant thereof comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to a corresponding parent CDR-L sequence described in TABLE 11.TABLE 11. Exemplary CDR-L sequences of antibodies for binding to IL-6

[0128] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the CDR-Ls described in TABLE 11, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodies described herein comprise at least one modification within any one of framework regions, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is IL-6, a functional fragment thereof, a variant thereof, a multimeric form thereof or a combination thereof. In some embodiments, the multispecific antibodies comprising the at least one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more increase in binding affinity for the target peptide in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pH condition relative to a corresponding binding affinity prior to the at least one modification.

[0129] In some embodiments, multispecific molecules described herein comprise a combination of CDRs, wherein the CDRs comprises a CDR-H1 or a variant thereof, a CDR-H2 or a variant thereof, a CDR-H3 or a variant thereof, a CDR-L 1 or a variant thereof, a CDR-L2 or a variant thereof, and a CDR- LS or a variant thereof, and wherein the combination is according to any one of the combinations provided in TABLE 12.TABLE 12. Exemplary CDR sequences of antibodies for binding to IL-6

[0130] In some embodiments, multispecific molecules described herein comprise an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least90%, at least 95% or 100% identical to any one of VL sequences described in TABLE 13, wherein themultispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%,80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 221.TABLE 13. Exemplary VL sequence of antibodies for binding to IL-6

[0131] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the VL sequences described in TABLE 13, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodies described herein comprise at least one modification within any one of framework regions, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is IL-6, a functional fragment thereof, a variant thereof, a multimeric form thereof or a combination thereof. In some embodiments, the multispecific antibodies comprising the at least one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more increase in binding affinity for the target peptide in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pHcondition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, multispecific antibodies described herein comprise two light chain variable region that are at least 90%, at least 95%, at least 98% or 100% identical relative to each other.

[0132] In some embodiments, multispecific antibodies comprise an IL-6 binding region, wherein the IL-6 binding region comprises an IL-6 binding heavy chain variable domain and, optionally, an IL-6 binding light chain variable domain. In some embodiments, multispecific antibodies described herein comprise a binding affinity for IL-6, a variant thereof or a functional fragment thereof that is at least 10%, at least 20%, at least 30%, at least 50%, at least 80%, at least 100%, at least 200% or more higher under neutral pH condition relative to the binding affinity under acidic pH condition. In some embodiments, multispecific antibodies described herein comprise a ratio of binding affinities for IL-6, a variant thereof or a functional fragment under neutral pH condition and acidic pH condition is at least 1.1, 1.5, 2, 3, 5, 8, 10, 100 or more. In some embodiments, multispecific antibodies described herein comprise a binding affinity for IL-6, a variant thereof or a functional fragment thereof that is at least 10%, at least 20%, at least 30%, at least 50%, at least 80%, at least 100%, at least 200% or more higher at about pH 7.4 relative to the binding affinity at about pH 5.8. In some embodiments, multispecific antibodies described herein comprise a ratio of binding affinities for IL-6, a variant thereof or a functional fragment at about pH 7.4 and about pH 5.8 is at least 1.1, 1.5, 2, 3, 5, 8, 10, 100 or more.

[0133] In some embodiments, multispecific molecules described herein comprise: (a) a VH sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of amino acid sequences described in TABLE 10; and (b) a VL sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of amino acid sequences described in TABLE 13, wherein the multispecific molecule comprises the VH sequence and the VL sequence according to the combination described in TABLE 14.TABLE 14. Exemplary VH and VL sequences of antibodies for binding IL-6IL-12

[0134] Interleukin- 12 (IL- 12) is a heterodimeric cytokine comprising p40 subunit of IL- 12 (IL- 12p40) and p35 subunit of IL-12 (IL-12p35). Accordingly, the IL-12 family, as described herein, include IL 12, IL-12p40, IL-12p35, a functional fragment thereof, a variant thereof, a multimeric formthereof or a combination thereof. Amino acid sequences of IL- 12 family proteins are recited in TABLE 15.TABLE 15. Amino Acid Sequences of IL-12

[0135] In some embodiments, multispecific molecules described herein bind to IL- 12, a subunit thereof, a functional fragment thereof, a variant thereof, a multimeric form thereof or a combination thereof. In some embodiments, multispecific molecules bind to an amino acid sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequences recited in TABLE 15. In some embodiments, multispecific molecules bind to an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 270. In some embodiments, multispecific molecules bind to an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 271.

[0136] In some embodiments, multispecific molecules described herein comprise at least one of CDR- Hs described in TABLE 16 or a variant thereof, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOs: 272-280. In some embodiments, multispecific molecules described herein comprise any one of CDR-H1 described in TABLE 16 or a variant thereof, any one of CDR-H2 described in TABLE 16 or a variant thereof, and any one of CDR-H3 described in TABLE 16 or a variant thereof, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 271. In some embodiments, multispecific molecules described herein comprise any one of combinations of CDR-Hs or variants thereof described in TABLE 16, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 271. In some embodiments, the CDR-H variant comprises at least one, at leasttwo or at least three substitutions, deletions, additions or combination thereof relative to a corresponding parent CDR-H sequence described in TABLE 16. In some embodiments, the CDR-H or the variant thereof comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to a corresponding parent CDR- H sequence described in TABLE 16.TABLE 16. Exemplary CDR-H sequences of antibodies for binding to IL-12

[0137] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the CDR-Hs described in TABLE 16, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodies described herein comprise at least one modification within any one of framework regions, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is IL- 12, a subunit thereof, a functional fragment thereof, a variant thereof, a multimeric form thereof or a combination thereof. In some embodiments, the multispecific antibodies comprising the at least one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more increase in binding affinity for the target peptide in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pH condition relative to a corresponding binding affinity prior to the at least one modification.

[0138] In some embodiments, multispecific molecules described herein comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of VH sequences described in TABLE 17, wherein themultispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 271.TABLE 17. Exemplary VH sequence of antibodies for binding to IL-12

[0139] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the VH sequences described in TABLE 17, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodies described herein comprise at least one modification within any one of framework regions, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is IL- 12, a subunit thereof, a functional fragment thereof, a variant thereof, a multimeric form thereof or a combination thereof. In some embodiments, the multispecific antibodies comprising the at least one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more increase in binding affinity for the target peptide in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pH condition relative to a corresponding binding affinity prior to the at least one modification.

[0140] In some embodiments, multispecific molecules described herein comprise at least one of CDR- Ls described in TABLE 18 or a variant thereof, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100%identical to SEQ ID NO: 271. In some embodiments, multispecific molecules described herein comprise any one of CDR-L 1 described in TABLE 18 or a variant thereof, any one of CDR-L2 described in TABLE 18 or a variant thereof, and any one of CDR-L3 described in TABLE 18 or a variant thereof, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 271. In some embodiments, multispecific molecules described herein comprise any one of combinations of CDR-Ls or variants thereof described in TABLE 18, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 271. In some embodiments, the CDR-L variant comprises at least one, at least two or at least three substitutions, deletions, additions or combination thereof relative to a corresponding parent CDR-L sequence described in TABLE 18. In some embodiments, the CDR-L or the variant thereof comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to a corresponding parent CDR-L sequence described in TABLE 18.TABLE 18. Exemplary CDR-L sequences of antibodies for binding to IL-12

[0141] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the CDR-Ls described in TABLE 18, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodies described herein comprise at least one modification within any one of framework regions, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is IL- 12, a subunit thereof, a functional fragment thereof, a variant thereof, a multimeric form thereof or a combination thereof. In some embodiments, the multispecific antibodies comprising the at least one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or moreincrease in binding affinity for the target peptide in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pH condition relative to a corresponding binding affinity prior to the at least one modification.

[0142] In some embodiments, multispecific molecules described herein comprise a combination of CDRs, wherein the CDRs comprises a CDR-H1 or a variant thereof, a CDR-H2 or a variant thereof, a CDR-H3 or a variant thereof, a CDR-L 1 or a variant thereof, a CDR-L2 or a variant thereof, and a CDR- L3 or a variant thereof, and wherein the combination is according to any one of the combinations provided in TABLE 19.TABLE 19. Exemplary CDR sequences of antibodies for binding to IL-12

[0143] In some embodiments, multispecific molecules described herein comprise an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of VL sequences described in TABLE 20, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 271.TABLE 20. Exemplary VL sequence of antibodies for binding to IL-12

[0144] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the VL sequences described in TABLE 20, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodies described herein comprise at least one modification within any one of framework regions, wherein theat least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is IL- 12, a subunit thereof, a functional fragment thereof, a variant thereof, a multimeric form thereof or a combination thereof. In some embodiments, the multispecific antibodies comprising the at least one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more increase in binding affinity for the target peptide in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, multispecific antibodies described herein comprise two light chain variable region that are at least 90%, at least 95%, at least 98% or 100% identical relative to each other.

[0145] In some embodiments, multispecific antibodies comprise an IL- 12 binding region, wherein the IL-12 binding region comprises an IL-12 binding heavy chain variable domain and, optionally, an IL- 12 binding light chain variable domain. In some embodiments, multispecific antibodies described herein comprise a binding affinity for IL- 12, a variant thereof or a functional fragment thereof that is at least 10%, at least 20%, at least 30%, at least 50%, at least 80%, at least 100%, at least 200% or more higher under neutral pH condition relative to the binding affinity under acidic pH condition. In some embodiments, multispecific antibodies described herein comprise a ratio of binding affinities for IL-12, a variant thereof or a functional fragment under neutral pH condition and acidic pH condition is at least 1.1, 1.5, 2, 3, 5, 8, 10, 100 or more. In some embodiments, multispecific antibodies described herein comprise a binding affinity for IL- 12, a variant thereof or a functional fragment thereof that is at least 10%, at least 20%, at least 30%, at least 50%, at least 80%, at least 100%, at least 200% or more higher at about pH 7.4 relative to the binding affinity at about pH 5.8. In some embodiments, multispecific antibodies described herein comprise a ratio of binding affinities for IL- 12, a variant thereof or a functional fragment at about pH 7.4 and about pH 5.8 is at least 1.1, 1.5, 2, 3, 5, 8, 10, 100 or more.

[0146] In some embodiments, multispecific molecules described herein comprise: (a) a VH sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of amino acid sequences described in TABLE 17; and (b) a VL sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of amino acid sequences described in TABLE 20, wherein the multispecific molecule comprises the VH sequence and the VL sequence according to thecombination described in TABLE 21.TABLE 21. Exemplary VH and VL sequences of antibodies for binding IL-12IL-23

[0147] Interleukin-23 (IL-23) is a heterodimeric cytokine comprising pl9 subunit of IL-23 (IL- 23pl9) and IL-12p40. Accordingly, the IL-23 family, as described herein, includes IL-23, IL-23pl9, IL-12p40, a functional fragment thereof, a variant thereof, a multimeric form thereof or a combination thereof. Amino acid sequences of IL-23pl9 and IL-12p40 are recited in TABLE 22.TABLE 22. Amino Acid Sequences of IL-23

[0148] In some embodiments, multispecific molecules described herein bind to IL-23, a subunit thereof, a functional fragment thereof, a variant thereof, a multimeric form thereof or a combination thereof. In some embodiments, the multispecific molecules bind to an amino acid sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequences recited in TABLE 22. In some embodiments, multispecific molecules bind to an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 304. In some embodiments, multispecific molecules bind to an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQID NO: 271

[0149] In some embodiments, multispecific molecules described herein comprise at least one of CDR- Hs described in TABLE 23 or a variant thereof, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100%identical to any one of SEQ ID NOs: 305-370. In some embodiments, multispecific molecules described herein comprise any one of CDR-H1 described in TABLE 23 or a variant thereof, any one of CDR-H2 described in TABLE 23 or a variant thereof, and any one of CDR-H3 described in TABLE 23 or a variant thereof, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 304. In some embodiments, multispecific molecules described herein comprise any one of combinations of CDR-Hs or variants thereof described in TABLE 23, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 304. In some embodiments, the CDR-H variant comprises at least one, at least two or at least three substitutions, deletions, additions or combination thereof relative to a corresponding parent CDR-H sequence described in TABLE 23. In some embodiments, the CDR-H or the variant thereof comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to a corresponding parent CDR- H sequence described in TABLE 23.TABLE 23. Exemplary CDR-H sequences of antibodies for binding to IL-23

[0150] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the CDR-Hs described in TABLE 23, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodies described herein comprise at least one modification within any one of framework regions, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is IL-23, a subunit thereof, a functional fragment thereof, a variant thereof, a multimeric form thereof or a combination thereof. In some embodiments, the multispecific antibodies comprising the at least one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more increase in binding affinity for the target peptide in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pH condition relative to a corresponding binding affinity prior to the at least one modification.

[0151] In some embodiments, multispecific molecules described herein comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of VH sequences described in TABLE 24, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 304.TABLE 24. Exemplary VH sequence of antibodies for binding to IL-23

[0152] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the VH sequences described in TABLE 24, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodies described herein comprise at least one modification within any one of framework regions, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is IL-23, a subunit thereof, a functional fragment thereof, a variant thereof, a multimeric form thereof or a combination thereof. In some embodiments, the multispecific antibodies comprising the at least one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or moreincrease in binding affinity for the target peptide in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pH condition relative to a corresponding binding affinity prior to the at least one modification.

[0153] In some embodiments, multispecific molecules described herein comprise at least one of CDR- Ls described in TABLE 25 or a variant thereof, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 304 In some embodiments, multispecific molecules described herein comprise any one of CDR-L 1 described in TABLE 25 or a variant thereof, any one of CDR-L2 described in TABLE 25 or a variant thereof, and any one of CDR-L3 described in TABLE 25 or a variant thereof, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 304. In some embodiments, multispecific molecules described herein comprise any one of combinations of CDR-Ls or variants thereof described in TABLE 25, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 304 In some embodiments, the CDR-L variant comprises at least one, at least two or at least three substitutions, deletions, additions or combination thereof relative to a corresponding parent CDR-L sequence described in TABLE 25. In some embodiments, the CDR-L or the variant thereof comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to a corresponding parent CDR-L sequence described in TABLE 25.TABLE 25. Exemplary CDR-L sequences of antibodies for binding to IL-23

[0154] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the CDR-Ls described in TABLE 25, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodies described herein comprise at least one modification within any one of framework regions, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is IL-23, a subunit thereof, a functional fragment thereof, a variant thereof, a multimeric form thereof or a combination thereof. In some embodiments, the multispecific antibodies comprising the at least one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more increase in binding affinity for the target peptide in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pH condition relative to a corresponding binding affinity prior to the at least one modification.

[0155] In some embodiments, multispecific molecules described herein comprise a combination of CDRs, wherein the CDRs comprises a CDR-H1 or a variant thereof, a CDR-H2 or a variant thereof, a CDR-H3 or a variant thereof, a CDR-L 1 or a variant thereof, a CDR-L2 or a variant thereof, and a CDR-L3 or a variant thereof, and wherein the combination is according to any one of the combinations provided in TABLE 26.TABLE 26. Exemplary CDR sequences of antibodies for binding to IL-23

[0156] In some embodiments, multispecific molecules described herein comprise an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of VL sequences described in TABLE 27, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 304.TABLE 27. Exemplary VL sequence of antibodies for binding to IL-23

[0157] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the VL sequences described in TABLE 27, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodies described herein comprise at least one modification within any one of framework regions, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is IL-23, a subunit thereof, a functional fragment thereof, a variant thereof, a multimeric form thereof or a combination thereof. In some embodiments, the multispecific antibodies comprising the at least one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more increase in binding affinity for the target peptide in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, multispecific antibodies described herein comprise two light chain variable region that are at least 90%, at least 95%, at least 98% or 100% identical relative to each other.

[0158] In some embodiments, the at least one modification in CDR-H1, CDR-H2d and / or CDR-H3. In some embodiments, the at least one modification is a substitution in CDR-H3. In some embodiments, the at least one modification comprises a substitution of an uncharged amino acid with a charged amino acid in CDR-H1, CDR-H2 and / or CDR-H3. In some embodiments, the at least one modification comprises a substitution of a charged amino acid with an uncharged amino acid in CDR-H1, CDR-H2 and / or CDR-H3. The uncharged amino acid can be an amino acid with a hydrophobic side chain (e.g., glycine, alanine, valine, cysteine, proline, leucine, isoleucine, methionine, tryptophan, phenylalanine). Alternatively, the uncharged amino acid can be a polar uncharged amino acid (e.g., serine, threonine, tyrosine, asparagine, glutamine). The charged amino acid can be a negatively charged amino acid (e.g., aspartic acid, glutamic acid). Alternatively, the charged amino acid can be a positively charged amino acid (e.g., lysine, arginine, histidine). In some embodiments, the at least one modification is asubstitution of a positively charged amino acid residue with a negatively charged amino acid residue in CDR-H1, CDR-H2 and / or CDR-H3. In some embodiments, the at least one modification is a substitution of a negatively charged amino acid residue with a positively charged amino acid residue in CDR-H1, CDR-H2 and / or CDR-H3. In some embodiments, a ratio of the binding affinities of target binding domains, variants thereof or functional fragments thereof, as described herein, for an IL-23, a variant thereof, or a fragment thereof at neutral pH and acidic pH, respective, is at least 1.2, at least 10, at least 100, at least 200, or more. In some embodiments, the VH sequence comprises an amino acid sequence of SEQ ID NO: 1544. In some embodiments, the VH sequence comprises at least one modification at positions selected from 28, 30, 31, 33, 34, 56, 58, 59, 62, 65, 98, 101, 102 and 108, relative to the amino acid position numbering of SEQ ID NO: 1544. In some embodiments, the VH sequence comprises at least one modification at positions selected from T28, T30, 131, A33, 134, G56, G58, H59, Q62, Q65, R98, E101, N102 and L108, relative to the amino acid position numbering of SEQ ID NO: 1544. In some embodiments, the VH sequence comprises at least one substitution selected from a group consisting of T28V, T28A, T28L, T28P, T30S, 13 IQ, A33T, I34M, I34V, G56K, G56A, G56N, G58A, H59Y, H59V, Q62S, Q62K, Q65R, Q65K, Q65A, R98I, E101S, E101Y, E101T, N102F, N102Y, N102S, N102D, N102K, N102R, L108T and L108M relative to the amino acid position numbering of SEQ ID NO: 1544.

[0159] In some embodiments, multispecific antibodies comprise an IL-23 binding region, wherein the IL-23 binding region comprises an IL-23 binding heavy chain variable domain and, optionally, an IL- 23 binding light chain variable domain. In some embodiments, multispecific antibodies described herein comprise a binding affinity for IL-23, a variant thereof or a functional fragment thereof that is at least 10%, at least 20%, at least 30%, at least 50%, at least 80%, at least 100%, at least 200% or more higher under neutral pH condition relative to the binding affinity under acidic pH condition. In some embodiments, multispecific antibodies described herein comprise a ratio of binding affinities for IL-23, a variant thereof or a functional fragment under neutral pH condition and acidic pH condition is at least 1.1, 1.5, 2, 3, 5, 8, 10, 100 or more. In some embodiments, multispecific antibodies described herein comprise a binding affinity for IL-23, a variant thereof or a functional fragment thereof that is at least 10%, at least 20%, at least 30%, at least 50%, at least 80%, at least 100%, at least 200% or more higher at about pH 7.4 relative to the binding affinity at about pH 5.8. In some embodiments, multispecific antibodies described herein comprise a ratio of binding affinities for IL-23, a variant thereof or a functional fragment at about pH 7.4 and about pH 5.8 is at least 1.1, 1.5, 2, 3, 5, 8, 10, 100 or more.

[0160] In some embodiments, multispecific molecules described herein comprise: (a) a VH sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of amino acid sequences described in TABLE 24; and (b) a VL sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of amino acid sequences described in TABLE 27, wherein the multispecific molecule comprises the VH sequence and the VL sequence according to thecombination described in TABLE 28.TABLE 28. Exemplary VH and VL sequences of antibodies for binding IL-23IL-17 and IL-17R Constructs

[0161] Interleukin- 17 (IL-17) family cytokine in humans comprises IL-17A, IL-17B, IL-17C, IL17- D, IL-17E and IL-17F. These cytokines are involved in proinflammatory responses and can mediate or induce the expression of a variety of other cytokines, factors, and mediators including tissue necrosis factor-alpha (TNF-a), IL-6, IL-8, IL- 1 , granulocyte colony-stimulating factor (G-CSF), prostaglandin E2 (PGE2), IL-10, IL-12, IL-1R antagonist, leukemia inhibitory factor, and stromelysin. IL-17 family cytokine also induces nitric oxide in chondrocytes and in human osteoarthritis explants. IL-17 family cytokine can induce the release of cytokines, chemokines, and growth factors and is an important local orchestrator of neutrophil accumulation. IL- 17 family cytokine can induce cartilage and bone destruction. IL- 17 family cytokine signaling is a target in a variety of autoimmune diseases including rheumatoid arthritis (RA), ankylosing spondylitis, psoriasis, hidradenitis suppurativa, ulcerative colitis, Crohn's disease, multiple sclerosis (MS), psoriatic arthritis, asthma, lupus (SLE), and sepsis.

[0162] In some embodiments, multispecific antibodies described herein bind an IL- 17 family cytokine amino acid sequence, or portion thereof. In some embodiments, multispecific antibodies described herein bind an IL-17A amino acid sequence, or portion thereof. In some embodiments, multispecific antibodies described herein bind an IL-17A / F amino acid sequence, or portion thereof. In some embodiments, antibodies targeting IL-17A or IL-17A / F are used for treating psoriasis (PsO), psoriatic arthritis (PsA), ankylosing spondylitis (AS), non-radiographic Axial Spondyloarthritis (nr- axSpA), Enthesitis-related arthritis (ERA) or combinations thereof.

[0163] In some embodiments, IL- 17 family cytokine functions as a heterodimer with an interleukin- 17 receptor (IL-17R) family of proteins. In some embodiments, the IL-17R comprises IL-17RA, IL- 17RB, IL-17RC, IL-17RD, IL-17RE, IL-17RF, or a combination thereof. Accordingly, in some embodiments, multispecific antibodies described herein are capable of binding any one of IL-17A, IL- 17B, IL-17C, IL-17D, IL-17E, IL-17F, IL-17RA, IL-17RB, IL-17RC, IL-17RD, IL-17RE, or a combination thereof.

[0164] Amino acid sequences of IL-17 family are recited in TABLE 29.TABLE 29. IL-17 and / or IL-17R Amino Acid Sequences

[0165] In some embodiments, multispecific molecules described herein bind to an amino acid sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to the sequences recited in TABLE 29. In some embodiments, multispecific molecules described herein bind to an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOS: 28-38.

[0166] In some embodiments, multispecific antibodies described herein comprise any one of combinations of CDR-Hs or variants thereof described in TABLE 30, wherein the multispecific antibody is capable of binding IL- 17 family cytokine, IL-17R or a combination thereof. In some embodiments, the CDR-H variant comprises at least one, two, or three substitutions, deletions, additions or combination thereof relative to a corresponding parent CDR-H sequence described in TABLE 30. In some embodiments, the CDR-H or the variant thereof comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to a corresponding parent corresponding parent CDR-H sequence described inTABLE 30TABLE 30. Exemplary CDR-H sequences of antibodies for binding to IL-17 and / or IL-17R

[0167] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the CDR-Hs described in TABLE 30, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodies described herein comprise at least one modification within any one of framework regions, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is an IL- 17 family cytokine amino acid sequence, or portion thereof. In some embodiments, the multispecific antibodies comprising the at least one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more increase in binding affinity for the target peptide in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pH condition relative to a corresponding binding affinity prior to the at least one modification.

[0168] In some embodiments, multispecific antibodies described herein comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of VH sequences described in TABLE 31, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOS: 28-38.TABLE 31. Exemplary VH sequence of antibodies for binding to IL-17 and / or IL-17R

[0169] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the VH sequences described in TABLE 31, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodies described herein comprise at least one modification within any one of framework regions, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is an IL- 17 family cytokine amino acid sequence, or portion thereof. In some embodiments, the multispecific antibodies comprising the at least one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more increase in binding affinity for the target peptide in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pH condition relative to a corresponding binding affinity prior to the at least one modification.

[0170] In some embodiments, multispecific antibodies described herein comprise any one of combinations of CDR-Ls or variants thereof described in TABLE 32, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOS: 28-38. In some embodiments, multispecific molecules described herein comprise any one of CDR-L1 described in TABLE 32 or a variant thereof, any one of CDR-L2 described in TABLE 32 or a variant thereof, and any one of CDR-L3 described in TABLE 32 or a variant thereof, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOS: 28-38. In some embodiments, multispecific molecules described herein comprise any one of combinations of CDR-Ls or variants thereof described in TABLE 32, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOS: 28-38. In some embodiments, the CDR-L variant comprises at least one, at least two or at least three substitutions, deletions, additions or combination thereof relative to a corresponding parent CDR-L sequence described in TABLE 32. In some embodiments, the CDR-L or the variant thereof comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to a corresponding parent CDR-L sequence described in TABLE 32.TABLE 32. Exemplary CDR-L sequences of antibodies for binding to IL-17 and / or IL-17R

[0171] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the CDR-Ls described in TABLE 32, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodies described herein comprise at least one modification within any one of framework regions, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is an IL- 17 family cytokine amino acid sequence, or portion thereof. In some embodiments, the multispecific antibodies comprising the at least one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more increase in binding affinity for the target peptide in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pH condition relative to a corresponding binding affinity prior to the at least one modification.

[0172] In some embodiments, multispecific antibodies described herein comprise a combination of CDRs, wherein the CDRs comprises a CDR-H1 or a variant thereof, a CDR-H2 or a variant thereof, a CDR-H3 or a variant thereof, a CDR-L 1 or a variant thereof, a CDR-L2 or a variant thereof, and a CDR- LS or a variant thereof, and wherein the combination is according to any one of the combinationsprovided in TABLE 33.TABLE 33. Exemplary CDR sequences of antibodies for binding to IL-17 and / or IL-17R

[0173] In some embodiments, multispecific antibodies described herein comprise an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of VL sequences described in TABLE 34, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOS: 28-38.TABLE 34. Exemplary VL sequence sequences of antibodies for binding to IL-17 and / or IL-17R

[0174] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the VL sequences described in TABLE 34, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodies described herein comprise at least one modification within any one of framework regions, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is an IL- 17 family cytokine amino acid sequence, or portion thereof. In some embodiments, the multispecific antibodies comprising the at least one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more increase in binding affinity for the target peptide in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, multispecific antibodies described herein comprise two light chain variable region that are at least 90%, at least 95%, at least 98% or 100%identical relative to each other.

[0175] In some embodiments, multispecific antibodies comprise n IL- 17a binding region, wherein the IL- 17 binding region comprises an IL- 17 binding heavy chain variable domain and, optionally, an IL- 17 binding light chain variable domain. In some embodiments, multispecific antibodies described herein comprise a binding affinity for IL- 17, a variant thereof or a functional fragment thereof that is at least 10%, at least 20%, at least 30%, at least 50%, at least 80%, at least 100%, at least 200% or more higher under neutral pH condition relative to the binding affinity under acidic pH condition. In some embodiments, multispecific antibodies described herein comprise a ratio of binding affinities for IL- 17, a variant thereof or a functional fragment under neutral pH condition and acidic pH condition is at least 1.1, 1.5, 2, 3, 5, 8, 10, 100 or more. In some embodiments, multispecific antibodies described herein comprise a binding affinity for IL- 17, a variant thereof or a functional fragment thereof that is at least 10%, at least 20%, at least 30%, at least 50%, at least 80%, at least 100%, at least 200% or more higher at about pH 7.4 relative to the binding affinity at about pH 5.8. In some embodiments, multispecific antibodies described herein comprise a ratio of binding affinities for IL- 17, a variant thereof or a functional fragment at about pH 7.4 and about pH 5.8 is at least 1.1, 1.5, 2, 3, 5, 8, 10, 100 or more.

[0176] In some embodiments, multispecific antibodies described herein comprise: (a) a VH sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of amino acid sequences described in TABLE 31; and (b) a VL sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of amino acid sequences described in TABLE 34, wherein the multispecific molecule comprises the VH sequence and the VL sequence according to the combination described in TABLE 35.TABLE 35. Exemplary VH and VL sequences of antibodies for binding to IL-17 and / or IL-17RTL1A

[0177] Tumor necrosis factor (TNF)-like cytokine 1A (TL1A; HGNC: 11931, Entrez Gene: 9966, UniProtKB: 095150) is a type 2 transmembrane protein that self-assembles into stable trimers and binds to death receptor 3 (DR3). TL1A can also bind to TNFR2 to produce proinflammatory cytokines like IL-6, ROS, and then impairs mitochondrial dysfunction. TL1A is also known as Tumor Necrosis Factor Ligand Superfamily Member 15 TNFSF15), TL1, VEGI, TNLG1B, or VEGI192A. TL1A is mainly expressed as the membrane-bound form.

[0178] TL1A is constitutive expressed in immune cells (e.g., monocyte, macrophage, dendritic cell, and T cells) and non-immune cells (e.g., endothelial cells and synovial fibroblast cells). TL1A expression in immune cells (e.g., macrophages and dendritic cells) increased by TLR4, TLR11, or FcgR. In non-immune cells (e.g., endothelial cells), TL1A constitutively expressed and upregulated in response to TNFa stimulation.

[0179] TL1A is also expressed as soluble form (sTLIA) that is produced by alternative splicing or TNFa converting enzyme (TACCE) cleavage. sTLIA can be detected in serum and body fluids of patients with T cell -mediated inflammatory autoimmune diseases, e.g., rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis. STL1A / DR3 binding promotes proinflammatory cytokine secretion, lymphocyte proliferation and cell apoptosis. For example, sTLIA can bind to DR3 and initiate one of two downstream pathways to cause: (1) inflammation - TRADD is recruited to the cytoplasmic domain of DR3, and then further recruits TRAF2 and RIP1 to initiate and activate MAPKs, NFkB, and PI3K signaling to regulate expression of pro-inflammatory genes; or (2) apoptosis - TRADD is recruited to the cytoplasmic domain of DR3, and TRADD binds to FADD and RIP3 to activate Caspase-8 to form complexes. It, then, induces apoptotic cell death through caspase pathway (-3 and -7). sTLIA can bind to soluble decoy receptor 3 (DcR3). When DcR3 competitively binds to sTLIA, combination of sTLIA and DR3 may be destroyed and results in less lymphocyte activation, less pro-inflammatory cytokine production, and prevents apoptosis. DcR3 can bind to other ligands like FasL and LIGHT.

[0180] TL1A is associated with autoimmune conditions (e.g., rheumatoid arthritis, inflammatory bowel disease, psoriasis, primary biliary cirrhosis, systemic lupus erythematosus, ankylosing spondylitis). The autoimmune conditions and its relationship with the TL1A expression are summarized in TABLE 36TABLE 36. TL1A Expression and Autoimmune Conditions

[0181] In some embodiments, serum level of TL1A is significantly associated with progression of atherosclerotic plaque height in subjects having rheumatoid arthritis. In some embodiments, treatment of collagen-induced arthritis (CIA) mice with anti-TLIA antibody decreases total joint score and clinical inflammation. In some embodiments, TL1A gene knock-out results in improved clinical profiles for CIA mice relative to wildtype mice.

[0182] In some embodiments, TL1A affects epithelial to mesenchymal transition (EMT) and increases the barrier permeability (reduces tight function protein), resulting in causing colonic fibrosis and inflammatory responses in subjects having inflammatory bowel disease. In some embodiments, TL1A expression is elevated in subjects having Crohn’s disease. In some embodiments, anti-TLIA improves tissue inflammation and inhibited expression of fibrotic pathways.

[0183] In some embodiments, TL1A is predominantly expressed in psoriatic lesions, particularly in infiltrating inflammatory cells, keratinocytes, and vascular cells. In some embodiments, TL1A promotes production of IL- 17, which ultimately leads to early inflammation. In some embodiments, anti-TLIA antibody treatment alleviates histopathological changes. In some embodiments, TL1A can synergize with IL-23 to stimulate IL- 17 secretion in peripheral blood mononuclear cells (PBMCs), thereby aggravating the autoimmune condition.

[0184] In some embodiments, serum TL1A levels are higher in subjects having primary biliary cirrhosis (PBS). In some embodiments, TL1A is expressed in biliary epithelial cells, vascular cells and infiltrating mononuclear cells of PBC liver. In some embodiments, the subjects show decrease in serum TL1A level after treatment with ursodeoxycholic acid (UDCA).

[0185] In some embodiments, multispecific molecules described herein are capable of binding TL1A protein. In some embodiments, multispecific (e.g., bispecific, trispecific) molecules described herein that bind to a mammalian TL1A sequence. In some embodiments, the TL1A is a human homolog. In some embodiments, the TL1A is a murine homolog.

[0186] An amino acid sequence of a human TL1A protein is recited in TABLE 37.TABLE 37. Amino Acid Sequence of human TL1A protein

[0187] In some embodiments, multispecific molecules described herein bind to an amino acid sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to any one of the sequences recited in TABLE 37. In some embodiments, multispecific molecules described herein bind to an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to SEQ ID NO: 139.

[0188] In some embodiments, multispecific molecules described herein comprise at least one of CDR- Hs described in TABLE 38 or a variant thereof, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOS: 139-141. In some embodiments, multispecific molecules described herein comprise any one of CDR-H1 described in TABLE 38 or a variant thereof, any one of CDR-H2 described in TABLE 38 or a variant thereof, and any one of CDR-H3 described in TABLE 38 or a variant thereof, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOS: 139-141. In some embodiments, multispecific molecules described herein comprise any one of combinations of CDR-Hs or variants thereof described in TABLE 38, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOS: 139-141. In some embodiments, the CDR- H variant comprises at least one, at least two or at least three substitutions, deletions, additions or combination thereof relative to a corresponding parent CDR-H sequence described in TABLE 38. In some embodiments, the CDR-H or the variant thereof comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to a corresponding parent CDR-H sequence described in TABLE 38.TABLE 38. Exemplary CDR-H sequences of antibodies for binding to TL1A

[0189] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the CDR-Hs described in TABLE 38, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodies described herein comprise at least one modification within any one of framework regions, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is TL1A, a variant thereof or a functional fragment thereof. In some embodiments, the multispecific antibodies comprising the at least one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more increase in binding affinity for the target peptide in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pH condition relative to a corresponding binding affinity prior to the at least one modification.

[0190] In some embodiments, multispecific molecules described herein comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of VH sequences described in TABLE 39, wherein themultispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%,80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOS: 139-141.TABLE 39. Exemplary VH sequence sequences of antibodies for binding to TL1A

[0191] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the VH sequences described in TABLE 39, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodies described herein comprise at least one modification within any one of framework regions, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is TL1A, a variant thereof or a functional fragment thereof. In some embodiments, the multispecific antibodies comprising the at least one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more increase in binding affinity for the target peptide in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pH condition relative to a corresponding binding affinity prior to the at least one modification.

[0192] In some embodiments, multispecific molecules described herein comprise at least one of CDR- Ls described in TABLE 40 or a variant thereof, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOS: 139-141. In some embodiments, multispecific molecules described herein comprise any one of CDR-L1 described in TABLE 40 or a variant thereof, any one of CDR-L2 described in TABLE 40 or a variant thereof, and any one of CDR-L3 described in TABLE 40 or a variant thereof, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOS: 139-141. In some embodiments, multispecific molecules described herein comprise any one of combinations of CDR-Ls or variants thereof described in TABLE 40, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOS: 139-141. In some embodiments, the CDR-L variant comprises at least one, at least two or at least three substitutions, deletions, additions or combination thereof relative to a corresponding parent CDR-L sequence described in TABLE 40. In some embodiments, the CDR-L or the variant thereof comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to a corresponding parent CDR-L sequence described in TABLE 40.TABLE 40. Exemplary CDR-L sequences of antibodies for binding to TL1A

[0193] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the CDR-Ls described in TABLE 40, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodies described herein comprise at least one modification within any one of framework regions, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is TL1A, a variant thereof or a functional fragment thereof. In some embodiments, the multispecific antibodies comprising the at least one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more increase in binding affinity for the target peptide in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pH condition relative to a corresponding binding affinity prior to the at least one modification.

[0194] In some embodiments, multispecific molecules described herein comprise a combination of CDRs, wherein the CDRs comprises a CDR-H1 or a variant thereof, a CDR-H2 or a variant thereof, a CDR-H3 or a variant thereof, a CDR-L 1 or a variant thereof, a CDR-L2 or a variant thereof, and a CDR- LS or a variant thereof, and wherein the combination is according to any one of the combinationsprovided in TABLE 41.TABLE 41. Exemplary CDR sequences of antibodies for binding to TL1A

[0195] In some embodiments, multispecific molecules described herein comprise an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of VL sequences described in TABLE 42, wherein the multispecific molecule is capable of binding an amino acid sequence that is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to any one of SEQ ID NOS: 139-141.TABLE 42. Exemplary VL sequence sequences of antibodies for binding to TL1A

[0196] In some embodiments, multispecific antibodies described herein comprise at least one modification within any one of the VL sequences described in TABLE 42, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. Alternatively, in some embodiments, multispecific antibodies described herein comprise at least one modification within any one of framework regions, wherein the at least one modification changes isoelectric point (pl) of the multispecific antibodies relative to a corresponding pl prior to the at least one modification. In some embodiments, the at least one modification provides a pH-dependent binding activity for a target peptide to multispecific antibodies, wherein the target peptide is TL1A, a variant thereof or a functional fragment thereof. In some embodiments, the multispecific antibodies comprising the at least one modification have a binding affinity for the target peptide that is at least 60%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, 100% or more in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more increase in binding affinity for the target peptide in neutral pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, the multispecific antibodies comprising the at least one modification have at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more decrease in binding affinity for the target peptide in acidic pH condition relative to a corresponding binding affinity prior to the at least one modification. In some embodiments, multispecific antibodies described herein comprise two light chain variable region that are at least 90%, at least 95%, at least 98% or 100% identical relative to each other. In some embodiments, at least one amino acid modification in TL1A binding heavy chain variable region increases in vivo half-life of multispecific antibody by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to half-life of corresponding multispecific antibody prior to said at least one amino acid modification.

[0197] In some embodiments, the at least one modification in CDR-H3. In some embodiments, the at least one modification is a substitution in CDR-H3. In some embodiments, the at least one modification comprises a substitution of an uncharged amino acid with a charged amino acid in CDR-H3. The uncharged amino acid can be an amino acid with a hydrophobic side chain (e.g., glycine, alanine, valine, cysteine, proline, leucine, isoleucine, methionine, tryptophan, phenylalanine). Alternatively, the uncharged amino acid can be a polar uncharged amino acid (e.g., serine, threonine, tyrosine, asparagine, glutamine). The charged amino acid can be a negatively charged amino acid (e.g., aspartic acid, glutamic acid). Alternatively, the charged amino acid can be a positively charged amino acid (e.g., lysine, arginine, histidine). In some embodiments, the at least one modification is a substitution of a positively charged amino acid residue with a negatively charged amino acid residue in CDR-H3. In some embodiments, the at least one modification is a substitution of a negatively charged amino acidresidue with a positively charged amino acid residue in CDR-H3. In some embodiments, a ratio of the binding affinities of target binding domains, variants thereof or functional fragments thereof, as described herein, for an epitope present on TL1A, a variant thereof, or a fragment thereof at neutral pH and acidic pH, respective, is at least 1.2, at least 10, at least 100, at least 200, or more. In some embodiments, the VH sequence comprises an amino acid sequence of SEQ ID NO: 923. In some embodiments, the VH sequence comprises at least one modification at positions selected from the group consisting of 30, 68, 82, 82A, 100 and 100C, relative to SEQ ID NO: 923, per Kabat numbering. In some embodiments, the VH sequence comprises at least one modification at positions selected from the group consisting of S30, T68, L82, N82A, T100 and F100C, relative to the amino acid position numbering of SEQ ID NO: 923, per Kabat numbering. In some embodiments, the VH sequence comprises at least one modification at positions selected from the group consisting of 30, 69, 83, 84, 104 and 107, relative to the amino acid position numbering of SEQ ID NO: 923. In some embodiments, the VH sequence comprises at least one modification at positions selected from the group consisting of S30, T69, L83, N84, T104 and F107 relative to the amino acid position numbering of SEQ ID NO: 923. In some embodiments, the VH sequence comprises at least one substitution at positions selected from the group consisting of S30T, T69I, L83V, N84K, T104D, FI07N and F107D relative to the amino acid position numbering of SEQ ID NO: 923.

[0198] In some embodiments, multispecific antibodies comprise a TL1A binding region, wherein the TL1A binding region comprises a TL1A binding heavy chain variable domain and, optionally, a TL1A binding light chain variable domain. In some embodiments, multispecific antibodies described herein comprise a binding affinity for TL1A, a variant thereof or a functional fragment thereof that is at least 10%, at least 20%, at least 30%, at least 50%, at least 80%, at least 100%, at least 200% or more higher under neutral pH condition relative to the binding affinity under acidic pH condition. In some embodiments, multispecific antibodies described herein comprise a ratio of binding affinities for TL1A, a variant thereof or a functional fragment under neutral pH condition and acidic pH condition is at least 1.1, 1.5, 2, 3, 5, 8, 10, 100 or more. In some embodiments, multispecific antibodies described herein comprise a binding affinity for TL1A, a variant thereof or a functional fragment thereof is at least 10%, at least 20%, at least 30%, at least 50%, at least 80%, at least 100%, at least 200% or more higher at about pH 7.4 relative to the binding affinity at about pH 5.8. In some embodiments, multispecific antibodies described herein comprise a ratio of binding affinities for TL1A, a variant thereof or a functional fragment at about pH 7.4 and about pH 5.8 is at least 1.1, 1.5, 2, 3, 5, 8, 10, 100 or more. In some embodiments, multispecific antibodies described herein comprise a binding affinity for trimeric TL1A is at least 10%, at least 20%, at least 30%, at least 50%, at least 80%, at least 100%, at least 200% or more higher than the binding affinity for monomeric TL1A under neutral pH condition. In some embodiments, multispecific antibodies described herein comprise a binding affinity for trimeric TL1A is at least 10%, at least 20%, at least 30%, at least 50%, at least 80%, at least 100%, at least 200% or more higher than the binding affinity for monomeric TL1A at about pH 7.4.

[0199] In some embodiments, multispecific molecules described herein comprise: (a) a VH sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of amino acid sequences described in TABLE 39; and (b) a VL sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of amino acid sequences described in TABLE 42, wherein the multispecific molecule comprises the VH sequence and the VL sequence according to the combination described in TABLE 43.TABLE 43. Exemplary VH and VL sequences of antibodies for binding to TL1ABsAb

[0200] Described herein are antibodies that are multispecific. In some embodiments, the multispecific antibodies target two or more different epitopes of the same target. In some embodiments, the multispecific antibodies are bispecific antibodies (BsAb) or trispecific antibodies. In some embodiments, the BsAb co...

Claims

CLAIMSWhat is claimed is:

1. An IgG antibody construct comprising: a TL1A binding region that binds an epitope on TL1A, a variant thereof or a functional fragment thereof, and an IL-23 binding region that binds an epitope on IL-23, a variant thereof or a functional fragment thereof, wherein: said TL1A binding region comprises a TL1A binding heavy chain variable domain and a TL1A binding light chain variable domain, at least one amino acid modification in said TL1A binding heavy chain variable region and / or said TL1A binding light chain variable region, and said amino acid modification changes an isoelectric point (pl) of said IgG antibody construct relative to a pl of a corresponding IgG antibody construct prior to said amino acid modification, thereby resulting in pH-dependent binding activity for said TL1A in said IgG antibody construct, as measured by surface plasmon resonance spectroscopy.

2. The IgG antibody construct of claim 1, wherein said IL-23 binding region comprises: an IL-23 binding heavy chain variable domain and an IL-23 binding light chain variable domain, and at least one amino acid modification in said IL-23 binding heavy chain variable domain and / or said IL-23 binding light chain variable domain, wherein said amino acid modification changes an isoelectric point (pl) of said IgG antibody construct relative to a pl of a corresponding IgG antibody construct prior to said amino acid modification, thereby resulting in pH-dependent binding activity for said IL-23 in said IgG antibody construct, as measured by surface plasmon resonance spectroscopy.

3. An IgG antibody construct comprising: a TL1A binding region that binds an epitope on TL1A, a variant thereof or a functional fragment thereof, and an IL-23 binding region that binds an epitope on IL-23, a variant thereof or a functional fragment thereof, wherein: said TL1A binding region comprises a TL1A binding heavy chain variable domain, said IL-23 binding region comprises an IL-23 binding heavy chain variable domain, anda binding affinity of said TL1A binding region for said TL1A is at least 10% higher at pH 7.4 relative to said binding affinity at pH 5.8, as measured by surface plasmon resonance spectroscopy.

4. The IgG antibody construct of claim 3, wherein a binding affinity of said IL-23 binding region for said IL-23 is at least 10% higher at pH 7.4 relative to said binding affinity at pH 5.8, as measured by surface plasmon resonance spectroscopy.

5. An IgG antibody construct comprising: a TL1A binding region that binds an epitope on TL1A, a variant thereof or a functional fragment thereof, and an IL-23 binding region that binds an epitope on IL-23, a variant thereof or a functional fragment thereof, wherein: said TL1A binding region comprises a TL1A binding heavy chain variable domain, and said IL-23 binding region comprises an IL-23 binding heavy chain variable domain.

6. The IgG antibody construct of claim 5, wherein a binding affinity of said TL1A binding region for said TL1A is higher than a binding affinity of said IL-23 binding region for said IL-23 under neutral pH condition, as measured by surface plasmon resonance spectroscopy.

7. The IgG antibody construct of claim 6, wherein said binding affinity of said TL1A binding region for said TL1A is at least two times higher than said binding affinity of said IL-23 binding region for said IL-23.

8. The IgG antibody construct of claim 5, wherein a binding affinity of said IL-23 binding region for said IL-23 is higher than a binding affinity of said TL1A binding region for said TL1A under neutral pH condition, as measured by surface plasmon resonance spectroscopy.

9. The IgG antibody construct of claim 8, wherein a binding affinity of said IL-23 binding region for said IL-23 is at least two times higher than a binding affinity of said TL1A binding region for said TL1A.

10. The IgG antibody construct of any one of claims 3-9, wherein said IgG antibody construct comprises a TL1A binding light chain variable domain that interact with said TL1A binding heavy chain variable domain, thereby forming said TL1A binding region, said TL1A binding heavy chain variable domain and / or said TL1A binding light chain variable domain comprises at least one amino acid modification that(c) increases binding affinity of said TL1A binding region for said TL1A relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification under neutral pH condition, as measured by surface plasmon resonance spectroscopy, and / or(d) decreases binding affinity of said TL1A binding region for said TL1A relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification under acidic pH condition, as measured by surface plasmon resonance spectroscopy.

11. The IgG antibody construct of any one of claims 3-10, wherein: said IgG antibody construct comprises an IL-23 binding light chain variable domain that interact with said IL-23 binding heavy chain variable domain, thereby forming said IL-23 binding region, said IL-23 binding heavy chain variable domain and / or said IL-23 binding light chain variable domain comprises at least one amino acid modification that(c) increases binding affinity of said IL-23 binding region for said IL-23 relative to said binding affinity of corresponding IL-23 binding region prior to said at least one amino acid modification under neutral pH condition, as measured by surface plasmon resonance spectroscopy, and / or(d) decreases binding affinity of said IL-23 binding region for said IL-23 relative to said binding affinity of corresponding IL-23 binding region prior to said at least one amino acid modification under acidic pH condition, as measured by surface plasmon resonance spectroscopy.

12. The IgG antibody construct of any one of claims 1-2 and 10-11, wherein said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said TL1A binding heavy chain variable domain.

13. The IgG antibody construct of claim 12, wherein said at least one amino acid modification is within a CDR-H3 of said TL1A binding heavy chain variable domain.

14. The IgG antibody construct of claim 13, wherein said at least one amino acid modification comprises a substitution of at least one uncharged amino acid with a charged amino acid.

15. The IgG antibody construct of any one of claims 1-2 and 10-14, wherein said at least one amino acid modification is within at least one framework region of said TL1A binding heavy chain variable domain.

16. The IgG antibody construct of any one of claims 1-2 and 10-15, wherein said at least one amino acid modification is within a CDR-L1, a CDR-L2, and / or a CDR-L3 of said TL1A binding light chain variable domain.

17. The IgG antibody construct of any one of claims 1-2 and 10-16, wherein said at least one amino acid modification is within at least one framework region of said TL1A binding light chain variable domain.

18. The IgG antibody construct of any one of claims 1-2 and 10-17, wherein said at least one amino acid modification increases binding affinity of said TL1A binding region for said TL1A in neutral pH condition by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, atleast 40%, at least 50% or more relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy.

19. The IgG antibody construct of any one of claims 1-2 and 10-18, wherein said at least one amino acid modification reduces a binding affinity of said TL1A binding region for said TL1A in acidic pH condition by at least 10% relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy.

20. The IgG antibody construct of any one of claims 2 and 10-19, wherein said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said IL-23 binding heavy chain variable domain.

21. The IgG antibody construct of any one of claims 2 and 10-20, wherein said at least one amino acid modification is within at least one framework region of said IL-23 binding heavy chain variable domain.

22. The IgG antibody construct of any one of claims 2 and 11-21, wherein said at least one amino acid modification is within a CDR-L1, a CDR-L2, and / or a CDR-L3 of said IL-23 binding light chain variable domain.

23. The IgG antibody construct of any one of claims 1-2 and 10-22, wherein said at least one amino acid modification is within at least one framework region of said TL1A binding light chain variable domain.

24. The IgG antibody construct of any one of claims 1-2 and 10-23, wherein said at least one amino acid modification increases binding affinity of said IL-23 binding region for said IL-23 in neutral pH condition by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to said binding affinity of corresponding IL-23 binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy.

25. The IgG antibody construct of any one of claims 1-2 and 10-24, wherein said at least one amino acid modification reduces a binding affinity of said TL1A binding region for said TL1A in acidic pH condition by at least 10% relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy.

26. The IgG antibody construct of any one of claims 1-4 and 6-25, wherein said IL-23 binding heavy chain variable region further binds an epitope that is present on IL-12p40, a variant thereof or a functional fragment thereof.

27. The IgG antibody construct of any one of claims 1-26, wherein said IgG antibody construct has higher binding affinity for trimeric TL1A relative to monomeric TL1A under neutral pH condition.

28. The IgG antibody construct of any one of claims 1-26, wherein said IgG antibody construct has higher binding affinity for monomeric TL1A relative to trimeric TL1A under neutral pH condition.

29. The IgG antibody construct of any one of claims 1-28, wherein said IgG antibody construct has higher binding affinity for monomeric IL-23 relative to heterodimeric IL-23 under neutral pH condition.

30. The IgG antibody construct of any one of claims 1-28, wherein said IgG antibody construct has higher binding affinity for heterodimeric IL-23 relative to monomeric IL-23 under neutral pH condition.

31. The IgG antibody construct of any one of claims 2 and 11-30, wherein said TL1A binding light chain variable domain and said IL-23 binding light chain variable domain are at least 90%, at least 95%, at least 98% or 100% identical relative to each other.

32. The IgG antibody construct of any one of claims 1-2 and 10-31, wherein said at least one amino acid modification in said TL1A binding heavy chain variable domain increases half-life of said IgG antibody construct in vivo by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to half-life of corresponding IgG antibody construct prior to said at least one amino acid modification.

33. An IgG antibody construct comprising : a TL1A binding region that binds an epitope on TL1A, a variant thereof or a functional fragment thereof, and an IL-12 binding region that binds an epitope on IL-I2p40, IL-12p35, a variant thereof or a functional fragment thereof, wherein: said TL1A binding region comprises a TL1A binding heavy chain variable domain and a TL1A binding light chain variable domain, and at least one amino acid modification in said TL1A binding heavy chain variable domain and / or said TL1A binding light chain variable domain, and said amino acid modification changes an isoelectric point (pl) of said IgG antibody construct relative to a pl of a corresponding IgG antibody construct prior to said amino acid modification, thereby resulting in pH-dependent binding activity for said TL1A in said IgG antibody construct, as measured by surface plasmon resonance spectroscopy.

34. The IgG antibody construct of claim 33, wherein said IL-12 binding region comprises: an IL- 12 binding heavy chain variable domain and an IL- 12 binding light chain variable domain, and at least one amino acid modification in said IL- 12 binding heavy chain variable domain and / or said IL- 12 binding light chain variable domain,wherein said amino acid modification changes an isoelectric point (pl) of said IgG antibody construct relative to a pl of a corresponding IgG antibody construct prior to said amino acid modification, thereby resulting in pH-dependent binding activity for said IL-12 in said IgG antibody construct, as measured by surface plasmon resonance spectroscopy.

35. An IgG antibody construct comprising : a TL1A binding region that binds an epitope on TL1A, a variant thereof or a functional fragment thereof, and an IL-12 binding region that binds an epitope on IL-I2p40, IL-12p35, a variant thereof or a functional fragment thereof, wherein: said TL1A binding region comprises a TL1A binding heavy chain variable domain, said IL- 12 binding region comprises an IL- 12 binding heavy chain variable domain, and a binding affinity of said TL1A binding region for said TL1A is at least 10% higher at pH 7.4 relative to said binding affinity at pH 5.8, as measured by surface plasmon resonance spectroscopy.

36. The IgG antibody construct of claim 35, wherein a binding affinity of said IL- 12 binding region for said IL-12 is at least 10% higher at pH 7.4 relative to said binding affinity at pH 5.8, as measured by surface plasmon resonance spectroscopy.

37. An IgG antibody construct comprising: a TL1A binding region that binds an epitope on TL1A, a variant thereof or a functional fragment thereof, and an IL-12 binding region that binds an epitope on IL-12p40, IL-12p35, a variant thereof or a functional fragment thereof, wherein: said TL1A binding region comprises a TL1A binding heavy chain variable domain, said IL- 12 binding region comprises an IL- 12 binding heavy chain variable domain, and a binding affinity of the TL1A binding region for said TL1A is more than four times a binding affinity of the IL- 12 binding region for said IL- 12 under neutral pH condition, as measured by surface plasmon resonance spectroscopy.

38. An IgG antibody construct comprising : a TL1A binding region that binds an epitope on TL1A, a variant thereof or a functional fragment thereof, and an IL-12 binding region that binds an epitope on IL-I2p40, IL-12p35, a variant thereof or a functional fragment thereof, wherein:said TL1A binding region comprises a TL1A binding heavy chain variable domain, said IL- 12 binding region comprises an IL- 12 binding heavy chain variable domain, and a binding affinity of the IL- 12 binding region for said IL- 12 is higher than a binding affinity of the TL1A binding region for said TL1A under neutral pH condition, as measured by surface plasmon resonance spectroscopy.

39. The IgG antibody construct of claim 38, wherein a binding affinity of the IL-12 binding region for said IL- 12 is at least two times higher than a binding affinity of the TL1A binding region for said TL1A.

40. The IgG antibody construct of any one of claims 35-39, wherein said IgG antibody construct comprises a TL1A binding light chain variable domain that interact with said TL1A binding heavy chain variable domain, thereby forming said TL1A binding region, said TL1A binding heavy chain variable domain and / or said TL1A binding light chain variable domain comprises at least one amino acid modification that(a) increases binding affinity of said TL1A binding region for said TL1A relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification under neutral pH condition, as measured by surface plasmon resonance spectroscopy, and / or(b) decreases binding affinity of said TL1A binding region for said TL1A relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification under acidic pH condition, as measured by surface plasmon resonance spectroscopy.

41. The IgG antibody construct of any one of claims 35-40, wherein: said IgG antibody construct comprises an IL- 12 binding light chain variable domain that interact with said IL- 12 binding heavy chain variable domain, thereby forming said IL- 12 binding region, said IL- 12 binding heavy chain variable domain and / or said IL- 12 binding light chain variable domain comprises at least one amino acid modification that(a) increases binding affinity of said IL- 12 binding region for said IL- 12 relative to said binding affinity of corresponding IL-12 binding region prior to said at least one amino acid modification under neutral pH condition, as measured by surface plasmon resonance spectroscopy, and / or(b) decreases binding affinity of said IL- 12 binding region for said IL- 12 relative to said binding affinity of corresponding IL-12 binding region prior to said at least one amino acid modification under acidic pH condition, as measured by surface plasmon resonance spectroscopy.

42. The IgG antibody construct of any one of claims 34-35 and 40-41, wherein said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said TL1A binding heavy chain variable domain.

43. The IgG antibody construct of claim 42, wherein said at least one amino acid modification is within a CDR-H3 of said TL1A binding heavy chain variable domain.

44. The IgG antibody construct of claim 43, wherein said at least one amino acid modification comprises a substitution of at least one uncharged amino acid with a charged amino acid.

45. The IgG antibody construct of any one of claims 34-35 and 40-44, wherein said at least one amino acid modification is within at least one framework region of said TL1A binding heavy chain variable domain.

46. The IgG antibody construct of any one of claims 35 and 40-45, wherein said at least one amino acid modification is within a CDR-L1, a CDR-L2, and / or a CDR-L3 of said TL1A binding light chain variable domain.

47. The IgG antibody construct of any one of claims 35 and 40-46, wherein said at least one amino acid modification is within at least one framework region of said TL1A binding light chain variable domain.

48. The IgG antibody construct of any one of claims 33-34 and 40-47, wherein said at least one amino acid modification increases binding affinity of said TL1A binding region for said TL1A in neutral pH condition by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy.

49. The IgG antibody construct of any one of claims 33-34 and 40-48, wherein said at least one amino acid modification reduces a binding affinity of said TL1A binding region for said TL1A in acidic pH condition by at least 10% relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy.

50. The IgG antibody construct of any one of claims 40-49, wherein said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said IL-12 binding heavy chain variable domain.

51. The IgG antibody construct of any one of claims 34 and 40-50, wherein said at least one amino acid modification is within at least one framework region of said IL- 12 binding heavy chain variable domain.

52. The IgG antibody construct of any one of claims 34 and 41-51, wherein said at least one amino acid modification is within a CDR-L1, a CDR-L2, and / or a CDR-L3 of said IL- 12 binding light chain variable domain.

53. The IgG antibody construct of any one of claims 33-34 and 40-52, wherein said at least one amino acid modification increases binding affinity of said IL- 12 binding region for said IL- 12 in neutral pH condition by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to binding affinity of corresponding IL- 12 binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy.

54. The IgG antibody construct of any one of claims 33-36 and 40-53, wherein said at least one amino acid modification reduces a binding affinity of said TL1A binding region for said TL1A in acidic pH condition by at least 10% relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy.

55. The IgG antibody construct of any one of claims 35-54, wherein said IL-12 binding heavy chain variable domain further binds an epitope that is present on IL-23, a variant thereof or a functional fragment thereof.

56. The IgG antibody construct of any one of claims 33-55, wherein said IgG antibody construct has higher binding affinity for trimeric TL1A relative to monomeric TL1A under neutral pH condition.

57. The IgG antibody construct of any one of claims 33-55, wherein said IgG antibody construct has higher binding affinity for monomeric TL1A relative to trimeric TL1A under neutral pH condition.

58. The IgG antibody construction of any one of claims 34 and 41-57, wherein said TL1A binding light chain variable domain and said IL- 12 binding light chain variable domain are at least 90%, at least 95%, at least 98% or 100% identical relative to each other.

59. The IgG antibody construct of any one of claims 33-34 and 40-58, wherein said at least one amino acid modification in said TL1A binding heavy chain variable domain increases half-life of said IgG antibody construct in vivo by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to half-life of corresponding IgG antibody construct prior to said at least one amino acid modification.

60. An IgG antibody construct comprising: a TL1A binding region that binds an epitope on TL1A, a variant thereof or a functional fragment thereof, and a second binding region that binds a second epitope on IL-6R, IL-6, IL- 17 family cytokine, IL- I7R, a variant thereof or a functional fragment thereof, wherein: said TL1A binding region comprises a TL1A binding heavy chain variable domain and a TL1A binding light chain variable domain,at least one amino acid modification in said TL1A binding heavy chain variable domain and / or said TL1A binding light chain variable domain, and said amino acid modification changes an isoelectric point (pl) of said IgG antibody construct relative to a pl of a corresponding IgG antibody construct prior to said amino acid modification, thereby resulting in pH-dependent binding activity for said TL1A in said IgG antibody construct, as measured by surface plasmon resonance spectroscopy.

61. The IgG antibody construct of claim 60, wherein said second binding region comprises: a second binding heavy chain variable domain and a second binding light chain variable domain, and at least one amino acid modification in said second binding heavy chain variable domain and / or said second binding light chain variable domain, wherein said amino acid modification changes an isoelectric point (pl) of said IgG antibody construct relative to a pl of a corresponding IgG antibody construct prior to said amino acid modification, thereby resulting in pH-dependent binding activity for said second epitope in said IgG antibody construct, as measured by surface plasmon resonance spectroscopy.

62. An IgG antibody construct comprising: a TL1A binding region that binds an epitope on TL1A, a variant thereof or a functional fragment thereof, and a second binding region that binds a second epitope on IL-6R, IL-6, IL- 17 family cytokine, IL- I7R, a variant thereof or a functional fragment thereof, wherein: said TL1A binding region comprises a TL1A binding heavy chain variable domain, said second binding region comprises a second binding heavy chain variable domain, and a binding affinity of said TL1A binding region for said TL1A is at least 10% higher at pH 7.4 relative to said binding affinity at pH 5.8, as measured by surface plasmon resonance spectroscopy.

63. The IgG antibody construct of claim 62, wherein a binding affinity of said second binding region for said second epitope is at least 10% higher at pH 7.4 relative to said binding affinity at pH 5.8, as measured by surface plasmon resonance spectroscopy.

64. An IgG antibody construct comprising: a TL1A binding region that binds an epitope on TL1A, a variant thereof or a functional fragment thereof, and an second binding region that binds a second epitope on IL-6R, IL-6, IL- 17 family cytokine, IL-17R, a variant thereof or a functional fragment thereof, wherein:said TL1A binding region comprises a TL1A binding heavy chain variable domain, and said second binding region comprises a second binding heavy chain variable domain.

65. The IgG antibody construct of claim 64, wherein a binding affinity of said TL1A binding region for said TL1A is higher than a binding affinity of said second binding region for said second epitope under neutral pH condition, as measured by surface plasmon resonance spectroscopy.

66. The IgG antibody construct of claim 65, wherein said binding affinity of said TL1A binding region for said TL1A is at least two times higher than said binding affinity of said second binding region for said second epitope.

67. The IgG antibody construct of claim 64, wherein a binding affinity of said second binding region for said second epitope is higher than a binding affinity of said TL1A binding region for said TL1A under neutral pH condition, as measured by surface plasmon resonance spectroscopy.

68. The IgG antibody construct of claim 67, wherein a binding affinity of said second binding region for said second epitope is at least two times higher than a binding affinity of said TL1A binding region for said TL1A.

69. The IgG antibody construct of any one of claims 62-68, wherein said IgG antibody construct comprises a TL1A binding light chain variable domain that interact with said TL1A binding heavy chain variable domain, thereby forming said TL1A binding region, said TL1A binding heavy chain variable domain and / or said TL1A binding light chain variable domain comprises at least one amino acid modification that(c) increases binding affinity of said TL1A binding region for said TL1A relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification under neutral pH condition, as measured by surface plasmon resonance spectroscopy, and / or(d) decreases binding affinity of said TL1A binding region for said TL1A relative to said binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification under acidic pH condition, as measured by surface plasmon resonance spectroscopy.

70. The IgG antibody construct of any one of claims 62-69, wherein: said IgG antibody construct comprises a second binding light chain variable domain that interact with said second binding heavy chain variable domain, thereby forming said second binding region, said second binding heavy chain variable domain and / or said second binding light chain variable domain comprises at least one amino acid modification that(c) increases binding affinity of said second binding region second epitope relative to said binding affinity of corresponding second binding region prior to said at leastone amino acid modification under neutral pH condition, as measured by surface plasmon resonance spectroscopy, and / or(d) decreases binding affinity of said second binding region second epitope relative to said binding affinity of corresponding second binding region prior to said at least one amino acid modification under acidic pH condition, as measured by surface plasmon resonance spectroscopy.

71. The IgG antibody construct of any one of claims 60-61 and 69-70, wherein said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said TL1A binding heavy chain variable domain.

72. The IgG antibody construct of claim 71, wherein said at least one amino acid modification is within a CDR-H3 of said TL1A binding heavy chain variable domain.

73. The IgG antibody construct of claim 72, wherein said at least one amino acid modification comprises a substitution of at least one uncharged amino acid with a charged amino acid.

74. The IgG antibody construct of any one of claims 61 and 70-73, wherein said at least one amino acid modification is within at least one framework region of said second binding heavy chain variable domain.

75. The IgG antibody construct of any one of claims 61 and 70-74, wherein said at least one amino acid modification is within a CDR-L1, a CDR-L2, and / or a CDR-L3 of said second binding light chain variable domain.

76. The IgG antibody construct of any one of claims 61 and 70-75, wherein said at least one amino acid modification is within at least one framework region of said second binding light chain variable domain.

77. The IgG antibody construct of any one of claims 60-61 and 69-76, wherein said at least one amino acid modification increases binding affinity of said TL1A binding region for said TL1 A in neutral pH condition by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy.

78. The IgG antibody construct of any one of claims 60-61 and 69-77, wherein said at least one amino acid modification reduces binding affinity of said TL1A binding region for said TL1A in acidic pH condition by at least 10% relative to binding affinity of corresponding TL1A binding region prior to said at least one amino acid modification, as measured by surface plasmon resonance spectroscopy.

79. The IgG antibody construct of any one of claims 69-78, wherein said at least one amino acid modification is within a CDR-H1, a CDR-H2, and / or a CDR-H3 of said second binding heavy chain variable domain.

80. The IgG antibody construct of any one of claims 60-61 and 69-79, wherein said at least one amino acid modification is within at least one framework region of said second binding heavy chain variable domain.

81. The IgG antibody construct of any one of claims 60-80, wherein said IgG antibody construct has higher binding affinity for trimeric TL1A relative to monomeric TL1A under neutral pH condition.

82. The IgG antibody construct of any one of claims 60-81, wherein said IgG antibody construct has higher binding affinity for monomeric TL1A relative to trimeric TL1A under neutral pH condition.

83. The IgG antibody construct of any one of claims 61 and 69-82, wherein said TL1A binding light chain variable domain and said second binding light chain variable domain are at least 90%, at least 95%, at least 98% or 100% identical relative to each other.

84. The IgG antibody construct of any one of claims 60-61 and 69-83, wherein said at least one amino acid modification in said TL1A binding heavy chain variable domain increases half-life of said IgG antibody construct in vivo by at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to half-life of corresponding IgG antibody construct prior to said at least one amino acid modification.

85. The IgG antibody construct of any one of claims 1-84, wherein the IgG antibody construct is an antibody, a Fab2 antibody, a bis-scFv antibody, a diabody, a DVD-Ig, a TandAb, a tandem scFv- Fc, a one-armed tandem scFv-Fc, a DART, a DART-Fc, or a functional fragment thereof.

86. The IgG antibody construct of any one of claims 1-84, wherein the IgG antibody construct is an antibody, a variant thereof, or a functional fragment thereof.

87. The IgG antibody construct of any one of claims 1-86 further comprising a constant region, wherein: said constant region comprises a first Fc domain and / or a second Fc domain.

88. The IgG antibody construct of claim 87, wherein said first Fc domain and said second Fc domain are derived from IgG I, IgG2, IgG3 or IgG4.

89. The IgG antibody construct of claim 87, wherein said first Fc domain and said second Fc domain are derived from IgGl constant domain.

90. The IgG antibody construct of claim 89, wherein said first Fc domain and said second Fc domain independently comprise M252Y, S254T, and T256E substitutions.

91. The IgG antibody construct of claim 89 or 90, wherein said first Fc domain and said second Fc domain independently comprise L234A and L235A substitutions.

92. The IgG antibody construct of any one of claims 89-91, wherein said first Fc domain and said second Fc domain independently comprise P329G substitution.

93. The IgG antibody construct of any one of claims 89-92, wherein said first Fc domain comprises a knob modification and said second Fc domain comprises a hole modification, wherein:said knob modification comprises replacing an original amino acid residue from an interface of the Fc region with an amino acid residue selected from tyrosine and tryptophan, and said hole modification comprises replacing an original amino acid residue from the interface of the Fc region with an amino acid residue selected from serine, threonine, valine and alanine.

94. The IgG antibody construct of any one of claims 89-93, wherein the first Fc domain comprises at least two modifications at positions selected from L351, F405 and Y407, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, K392 and T394, per EU numbering.

95. The IgG antibody construct of any one of claims 89-94, wherein the first Fc domain comprises at least two modifications at positions selected from Q347, Y349, T350, K370, G371, D399 and S400, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T350, S354, E357, K360, Q362E, S364, N390, K409 and T411, per EU numbering.

96. The IgG antibody construct of any one of claims 89-95, wherein the first Fc domain comprises at least one substitution at positions selected from S354 and T366, per EU numbering, and the second Fc domain comprises at least one modification at positions selected from T366, L368 and Y407, per EU numbering.

97. The IgG antibody construct of any one of claims 89-96, wherein the first Fc domain comprises at least one substitution selected from S354 and T366W, per EU numbering, and the second Fc domain comprises at least one substitution selected from T366S. L368A, Y407T, and Y407V, per EU numbering.

98. The IgG antibody construct of any one of claims 89-97, wherein said constant region comprises at least one amino acid modifications, wherein said at least one amino acid modification increases binding affinity of said constant region for a neonatal fragment crystallizable receptor (FcRn) in acidic pH condition relative to said binding affinity of corresponding constant region prior to the at least one amino acid modification, and wherein a binding affinity of said constant region for said FcRn in neutral pH condition remains within 20% of corresponding binding affinity of said corresponding constant region prior to the at least one modification.

99. The IgG antibody construct of claim 98, wherein said binding affinity of said constant region for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in acidic pH condition relative to the corresponding constant region prior to the at least one modification.

100. The IgG antibody construct of claim 98 or 99, wherein said at least one modification decreases plasma clearance (CL), increases plasma retention time, or increases plasma half-life (t' / z) relativeto a corresponding IgG antibody construct prior to said at least one modification in said constant region.

101. The IgG antibody construct of any one of claims 98-100, wherein a binding affinity of said constant region for a FcRn is increased in neutral pH condition relative to said binding affinity of a corresponding constant region prior to said at least one modification, and wherein a binding affinity of said constant region for said FcRn in acidic pH condition remains within 20% of said binding affinity of corresponding constant region prior to said at least one modification.

102. The IgG antibody construct of claim 101, wherein said binding affinity of said constant region for said FcRn is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 50%, at least 70% or more in neutral pH condition relative to said binding affinity of corresponding constant region prior to the at least one modification.

103. The IgG antibody construct of claim 101 or 102, wherein the at least one modification increases plasma clearance of TL1A by the IgG antibody construct, compared to a corresponding plasma clearance by an IgG antibody construct prior to the at least one modification in the constant region.

104. An antibody construct comprising : a TL1A binding region that binds an epitope on TL1A, a variant thereof or a functional fragment thereof, wherein the TL1A binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises at least one modification at positions selected from S30, T69, L83, N84, T104 and F107, relative to the amino acid position numbering of SEQ ID NO: 923.

105. The antibody construct of claim 104, wherein the heavy chain variable region comprises at least one modification comprises a substitution selected from the group consisting of S30T, T69I, L83V, N84K, T104D, F107N and F107D, relative to the amino acid position numbering of SEQ ID NO: 923.

106. The antibody construct of claim 104 or 105, wherein the at least one modification improves binding interaction with H109, Hl 18 and / or H121 of TL1A comprising an amino acid sequencer of SEQ ID NO: 139.

107. An antibody construct comprising : an IL-23 binding region that binds an epitope on IL-23, a variant thereof or a functional fragment thereof, wherein the IL-23 binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises at least one modification at positions selected from T28, T30, 131, A33, 134, G56, G58, H59, Q62, Q65, R98, E101, N102 and L108 relative to the amino acid position numbering of SEQ ID NO: 1544.

108. The antibody construct of claim 107, the heavy chain variable region comprises at least one modification comprises a substitution selected from the group consisting of T28V, T28A, T28L, T28P, T30S, 13 IQ, A33T, I34M, I34V, G56K, G56A, G56N, G58A, H59Y, H59V, Q62S, Q62K,Q65R, Q65K, Q65A, R98I, E101S, E101Y, E101T, N102F, N102Y, N102S, N102D, N102K, N102R, L108T and L108M relative to the amino acid position numbering of SEQ ID NO: 1544.

109. A pharmaceutical composition comprising the IgG antibody construct of any one of claims 1- 103, or the antibody construct of any one of claims 104-108, and a pharmaceutically acceptable carrier.

110. A method of treating a disease or a condition, wherein the method comprises administering an effective amount of the IgG antibody construct of any one of claims 1-103, the antibody construct of any one of claims 104-108, or the pharmaceutical composition of claim 109 to a subject in need thereof results in treatment of a disease or condition.

111. The method of claim 110, wherein the disease or condition is related to impaired mitochondrial dysfunction.

112. The method of claim 110 or 111, wherein the disease or condition is selected from the group consisting of: rheumatoid arthritis, Crohn's Disease (CD), ulcerative colitis (UC), psoriatic arthritis, ankylosing spondylitis, psoriasis, primary biliary cirrhosis, systemic lupus erythematosus or combinations thereof.

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