Bispecific proteins

Abstract

The present invention relates to bispecific molecules for binding to CD80 and comprising: a) a first polypeptide for binding to CD80 and inhibiting the binding of PD-L1 to CD80; and b) a second polypeptide for binding to CD80 and inhibiting the binding of CD28 to CD80 and compositions comprising the same, and uses thereof.

Description

Bispecific proteinsField of the invention

[0001] The invention relates to bispecific proteins for binding to CD80, related fragments thereof, and use thereof for the treatment of various conditions such as inflammation and autoimmunity.Related application

[0002] This application claims priority from Australian provisional applicationAU 2023903541 , the entire contents of which are hereby incorporated by reference.Background of the invention

[0003] The costimulatory ligand CD80 and the inhibitory ligand PD-L1 interact in cis on the surface of antigen presenting cells including dendritic cells. In the context of the cis- CD80:PD-L1 complex, CD80 can still bind the costimulatory receptor CD28 on interacting T cells, but PD-L1 cannot bind the T cell inhibitor receptor PD1 . Hence, these complexes activate naive T cells by allowing DC surface CD80 to trigger CD28 signalling without inhibition by PD-L1 .

[0004] The APC-expressed co -stimulatory ligands CD80 and CD86 are also ligands for cell surface CTLA4, in addition to CD28.

[0005] Regulatory T cells (Tregs) constitutively express abundant CTLA4, and inhibit co-stimulation by an additional mechanism whereby CD80 and CD86 are depleted from the APC surface through CTLA4-mediated transendocytosis.

[0006] Due to the critical role of the CD80 / CD86 co -stimulatory pathway in promoting and maintaining immune response, therapeutic agents designed to antagonize the pathway are in clinical use for the treatment of autoimmune diseases and disorders. One approach has been the development of Abatacept (Orencia®), a CTLA4-lg fusion protein consisting of the extracellular binding domain of CTLA4 linked to the Fc domain of a human IgG. Abatacept was developed to inhibit CD80 / CD86-mediated co-stimulation and is approved for the treatment of rheumatoid arthritis (RA) and in clinical trials for a number of other autoimmune indications.

[0007] Another approach has been the development of anti-CD80 antibodies, some of which block the interaction of CD80 with CD28 and others which bind to the PD-L1 binding site on CD80. Thus, antibodies for binding to CD80 may have differing mechanisms of action and differing effects on the CD80 co-stimulatory pathway.

[0008] There is a need for improved and / or alternative compositions and methods for modulation of the CD80 co-stimulatory and PD-L1 checkpoint pathways.

[0009] Reference to any prior art in the specification is not an acknowledgment or suggestion that this prior art forms part of the common general knowledge in any jurisdiction or that this prior art could reasonably be expected to be understood, regarded as relevant, and / or combined with other pieces of prior art by a skilled person in the art.Summary of the invention

[0010] The present invention provides a bispecific molecule for binding to CD80 and comprising: a) a first polypeptide for binding to CD80 and inhibiting the binding of PD-L1 to CD80; and b) a second polypeptide for binding to CD80 and inhibiting the binding of CD28 to CD80.

[0011] Preferably, the first polypeptide is in the form of an antigen binding protein that binds to CD80 and thereby inhibits (eg prevents or reduces) the binding of PD-L1 thereto.

[0012] Optionally, the second polypeptide is in the form of a native binding partner of CD80, or a functional homologue or derivative of a native binding partner of CD80. Accordingly, in certain embodiments, the present invention provides a bispecific molecule for binding to CD80 and comprising: a) a first polypeptide for binding to CD80, preferably comprising an antigen binding domain for binding to CD80 and that inhibits the binding of PD-L1 to CD80; and b) a second polypeptide comprising a native binding partner of CD80, or a functional homologue or derivative thereof, that inhibits the binding of CD28 to CD80.

[0013] The native binding partner of CD80 is preferably CTLA4 (or a soluble derivative or fragment thereof).

[0014] Preferably the second polypeptide comprises at least the amino acid sequence of the ligand binding domain of a CTLA4 protein, wherein the sequence of the ligand binding domain is common to both the soluble and transmembrane forms of the CTLA4 protein.

[0015] The second polypeptide may comprise the amino acid sequence of the ligand binding domain of a CTLA4 protein, along with one or more amino acid residues C- terminal to the ligand binding domain. The one or more amino acid residues C-terminal to the ligand binding domain may be amino acid residues of the native soluble or transmembrane isoforms of CTLA4. Alternatively, the one or more amino acid residues may comprise a linker sequence.

[0016] Optionally, the second polypeptide is in the form of an antigen binding protein that binds to CD80 and thereby inhibits (eg prevents or reduces) the binding of CD28 to CD80. Accordingly, in further embodiments, the invention provides a bispecific molecule for binding to CD80 and comprising: a) a first antigen binding domain for binding to CD80 and that inhibits the binding of PD-L1 to CD80; and b) a second antigen binding domain for binding to CD80 and that inhibits the binding of CD28 to CD80.

[0017] It will be appreciated that such bispecific molecules may be in the form of a bispecific antigen binding protein and termed biparatopic antigen binding proteins.

[0018] It will be appreciated that such bispecific molecules may be in the form of a bispecific antibody and termed biparatopic antibodies.

[0019] As used herein, the term “biparatopic” refers to a molecule, e.g. an antigen binding protein, that binds to distinct, non-overlapping epitopes of an antigen. Accordingly, in the context of the present invention, the biparatopic molecules described herein bind to distinct, non-overlapping epitopes of CD80, such that the molecules i) liberate PD-L1 from its interaction with CD80 and ii) block or inhibit the interaction of CD28 with CD80.

[0020] It will be appreciated that the antigen proteins of the invention may be monovalent, or multivalent for the target epitopes, as further exemplified herein.

[0021] In any embodiment, the first and second polypeptides are joined to each other directly or via a linker. Suitable linkers for joining the polypeptides are known to the skilled person and described elsewhere herein.

[0022] It will be appreciated that the first and second polypeptides may be joined in any arrangement. For example, the N terminal region of the first polypeptide may be joined to the N or C terminus of the second polypeptide. Alternatively, the C terminal region of the first polypeptide may be joined to the N or C terminus of the second polypeptide. Further still, the first and second polypeptides may be joined via any amino acid residue within the internal region of the polypeptides (ie via a residue that is not at either N or C terminus).

[0023] Reference herein to a polypeptide or antigen binding protein that “binds to” CD80 (or CD28 antigen ligand, or B7-1 antigen) provides literal support for a protein or antibody that “binds specifically to” or “specifically binds to” a CD80.

[0024] In any embodiment, the first polypeptide for binding to CD80 is in the form of an antigen binding domain and comprises:FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4, andFR1 a - CDR1 a - FR2a - CDR2a - FR3a - CDR3a - FR4a, wherein:FR1 , FR2, FR3 and FR4 are each framework regions;CDR1 , CDR2 and CDR3 are each complementarity determining regions;FR1 a, FR2a, FR3a and FR4a are each framework regions;CDR1 a, CDR2a and CDR3a are each complementarity determining regions; wherein the sequence of any of the framework regions or complementarity determining regions are as described herein, preferably as described in the Tables 1 to 6, herein.

[0025] In any embodiment, CDR1 , CDR2 and CDR3 refer to complementarity determining regions from the variable heavy chain of an antibody (a VH), CDR1a, CDR2a and CDR3a are complementarity determining regions from the variable light chain of an antibody (a VL), or where CDR1 , CDR2 and CDR3 are complementarity determining regions from the VL, CDR1a, CDR2a and CDR3a are complementarity determining regions from VH. In such examples, the CDRs may be referred to as CDRH1 , CDRH2, CDRH3, CDRL1 , CDRL2 and CDRL3 as the case may be.

[0026] In preferred embodiments, a first polypeptide (ie a first antigen binding protein) as described herein and that inhibits the binding of PD-L1 to CD80 is capable of binding to or specifically binding to residues of the membrane distal IgV domain of human CD80 (corresponding to residues G34 to AMO of human CD80). Optionally, a first antigen binding protein as described herein does not bind to the region or portion of CD80 that is bound by PD-L1 , but upon binding to CD80, prevents or reduces the binding of PD-L1 to CD80.

[0027] In particularly preferred embodiments, the first antigen binding protein as described herein is capable of binding to or specifically binding to the region or portion of CD80 that is bound by PD-L1 . As described elsewhere herein, prevention of the binding of PD-L1 to CD80 may also be referred to as “PD-L1 liberation”.

[0028] In certain embodiments, upon binding to CD80, the first antigen binding protein does not inhibit the binding of CD28 to CD80.

[0029] In alternative embodiments, the first antigen binding protein inhibits the binding of CD28 to CD80 in addition to inhibiting the binding of PD-L1 to CD80.

[0030] In any embodiment, the first antigen binding protein for binding to CD80:- comprises a VH comprising a sequence as set forth in SEQ ID NO: 73 and a VL comprising a sequence as set forth in SEQ ID NO: 148;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 77 and a VL comprising a sequence as set forth in SEQ ID NO: 152; comprises a VH comprising a sequence as set forth in SEQ ID NO: 74 and a VL comprising a sequence as set forth in SEQ ID NO: 149;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 78 and a VL comprising a sequence as set forth in SEQ ID NO: 153;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 75, and a VL comprising a sequence as set forth in SEQ ID NO: 150;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 76, and a VL comprising a sequence as set forth in SEQ ID NO: 151 ; or- comprises a VH comprising a sequence as set forth in SEQ ID NO: 310, and a VL comprising a sequence as set forth in SEQ ID NO: 311 .

[0031] In any embodiment, the first antigen binding protein comprises a CDRH1 , a CDRH2 and / or a CDRH3 of an antigen binding domain having a variable heavy chain as defined in any one of SEQ ID NOs: 73, 74, 75, 76, 77, 78 or 310.

[0032] In any embodiment, first antigen binding protein comprises a CDRL1 , a CDRL2 and / or a CDRL3 of an antigen binding domain having a variable light chain as defined in any one of SEQ ID NOs: 148, 149, 150, 151 , 152, 153 or 311 .

[0033] In any embodiment, the first antigen binding protein comprises:- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 73, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 148;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 74, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 149;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 75, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 150;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 76, and a CDR1 , a CDR2 and a CDR3 ofan antigen binding domain having a variable light chain as defined in SEQ ID NO: 151 ;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 77, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 152; a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 78, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 153; or- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 310 and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 311.

[0034] In any embodiment, the first antigen binding protein described herein comprises:FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4 - linker - FR1 a - CDR1 a - FR2a - CDR2a - FR3a - CDR3a - FR4a.

[0035] As defined herein, the linker may be a chemical, one or more amino acids, or a disulphide bond formed between two cysteine residues.

[0036] In certain preferred embodiments, the first antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of (in order of N to C terminus or C to N terminus) SEQ ID NOs: 73 and 148.

[0037] In certain preferred embodiments, the first antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of (in order of N to C terminus or C to N terminus) SEQ ID NOs: 74 and 149.

[0038] In certain preferred embodiments, the first antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of (in order of N to C terminus or C to N terminus) SEQ ID NOs: 75 and 150.

[0039] In certain preferred embodiments, the first antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of (in order of N to C terminus or C to N terminus) SEQ ID NOs: 76 and 151 .

[0040] In certain preferred embodiments, the first antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of (in order of N to C terminus or C to N terminus) SEQ ID NOs: 77 and 152.

[0041] In certain preferred embodiments, the first antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of (in order of N to C terminus or C to N terminus) SEQ ID NOs: 78 and 153.

[0042] In certain preferred embodiments, the first antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of (in order of N to C terminus or C to N terminus) SEQ ID NOs: 310 and 311 .

[0043] In a particularly preferred embodiment, the first antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of, in order N to C terminus, SEQ ID NO: 148 and SEQ ID NO: 73 (ie VL to VH). Optionally the antigen binding protein comprises SEQ ID NO: 148 (VL) - linker - SEQ ID NO: 73 (VH).

[0044] In a particularly preferred embodiment, the first antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of, in order N to C terminus, SEQ ID NO: 149 and SEQ ID NO: 74 (ie VL to VH). Optionally the antigen binding protein comprises SEQ ID NO: 149 (VL) - linker - SEQ ID NO: 74 (VH).

[0045] In a particularly preferred embodiment, the first antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of, in order N to C terminus, SEQ ID NO: 150 and SEQ ID NO: 75 (ie VL to VH), optionally SEQ ID NO:150 (VL) - linker - SEQ ID NO: 75 (VH).

[0046] In a particularly preferred embodiment, the first antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of, in order N to C terminus, SEQ ID NO: 151 and SEQ ID NO: 76 (ie VL to VH), optionally SEQ ID NO:151 (VL) - linker - SEQ ID NO: 76 (VH).

[0047] In a particularly preferred embodiment, the first antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of, in order Nto C terminus, SEQ ID NO: 152 and SEQ ID NO: 77 (ie VL to VH), optionally SEQ ID NO:152 (VL) - linker - SEQ ID NO: 77 (VH).

[0048] In a particularly preferred embodiment, the first antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of, in order N to C terminus, SEQ ID NO: 153 and SEQ ID NO: 78 (ie VL to VH), optionally SEQ ID NO:153 (VL) - linker - SEQ ID NO: 78 (VH).

[0049] In a particularly preferred embodiment, the first antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of, in order N to C terminus, SEQ ID NO: 311 and SEQ ID NO: 310 (ie VL to VH), optionally SEQ ID NO: 31 1 (VL) - linker - SEQ ID NO: 310 (VH).

[0050] In any embodiment, the first antigen binding protein comprises:(i) a VH comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 1 (IMGT) or 13 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 2 (IMGT) or 14 or 353 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 3 (IMGT) or 15 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(ii) a VH comprising a sequence as set forth in SEQ ID NO: 73 or 77, or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iii) a VL comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 79 (IMGT) or 91 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 80 (IMGT) or 92 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 81 (IMGT or Kabat)or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iv) a VL comprising a sequence as set forth in SEQ ID NO: 148 or 152, or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(v) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 1 , a CDR2 comprising a sequence set forth in SEQ ID NO: 2, and a CDR3 comprising a sequence set forth in SEQ ID NO: 3; or comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 13, a CDR2 comprising a sequence set forth in SEQ ID NO: 14 or 353, and a CDR3 comprising a sequence set forth in SEQ ID NO: 15;(vi) a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 79, a CDR2 comprising a sequence set forth in SEQ ID NO: 80 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 81 ; or comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 91 , a CDR2 comprising a sequence set forth in SEQ ID NO: 92 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 81 ;(vii) a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 1 , a CDR2 comprising a sequence as set forth in SEQ ID NO: 2 and a CDR3 comprising asequence as set forth in SEQ ID NO: 3; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 79, a CDR2 comprising a sequence as set forth in SEQ ID NO: 80 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 81 ; or a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 13, a CDR2 comprising a sequence as set forth in SEQ ID NO: 14 or 353 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 15; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 91 , a CDR2 comprising a sequence as set forth in SEQ ID NO: 92 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 81 ; or(viii) a VH comprising a sequence as set forth in SEQ ID NO: 73 or 77; and a VL comprising a sequence set forth in SEQ ID NO: 148 or 152.

[0051] When the CDRs are determined according to the IMGT system, the first antigen binding domain may further comprise at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 25, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 26, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 27, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 28, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 101 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 102, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ IDNO: 103, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 104, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0052] When the CDRs are determined according to the Kabat system, the first antigen binding domain may further comprise at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 49, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 50, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 51 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 52, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 124, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 125, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 126, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 127, or a sequence at least about 80%, at least 85%, at least 90%, at least91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0053] When the CDRs are determined according to the IMGT system, the first antigen binding domain may further comprise at least one of:(I) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 41 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 42, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 43, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 44, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 105, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 106, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 107, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 108, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0054] When the CDRs are determined according to the Kabat system, the first antigen binding domain may further comprise at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 53, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 54, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 55, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 56, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 128, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 129, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 130, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 131 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0055] In any embodiment, the antigen binding protein comprises a variable heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 73, or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical thereto; and a variable light chain comprising the amino acid sequence as set forth in SEQ ID NO: 148; or a sequence at least about 80%, at least about 85%, at least about 90%, at leastabout 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98 %, or at least about 99% identical thereto; wherein the variable heavy and / or light chains comprise no more than 1 , no more than 2, no more than 3, no more than 4, no more than 5, no more than 6, no more than 7, no more than 8, no more than 9, no more than 10, no more than 11 , no more than 12, no more than 13, no more than 14, no more than 15, no more than 16, no more than 17, no more than 18, no more than 19 or no more than 20 amino acid residue substitutions, deletions, or additions or combination thereof, outside the indicated CDR sequences, and wherein the antigen binding protein retains the ability to bind to CD80.

[0056] In any embodiment, the antigen binding protein comprises a variable heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 77, or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical thereto; and a variable light chain comprising the amino acid sequence as set forth in SEQ ID NO: 152; or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98 %, or at least about 99% identical thereto; wherein the variable heavy and / or light chains comprise no more than 1 , no more than 2, no more than 3, no more than 4, no more than 5, no more than 6, no more than 7, no more than 8, no more than 9, no more than 10, no more than 11 , no more than 12, no more than 13, no more than 14, no more than 15, no more than 16, no more than 17, no more than 18, no more than 19 or no more than 20 amino acid residue substitutions, deletions, or additions or combination thereof, outside the indicated CDR sequences, and wherein the antigen binding protein retains the ability to bind to CD80.

[0057] In any embodiment, the first antigen binding domain comprises:(i) a VH comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 4 (IMGT) or 16 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 5 (IMGT) or 17 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 6 or 18 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(ii) a VH comprising a sequence as set forth in SEQ ID NO: 74 or 78, or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iii) a VL comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 82 (IMGT) or 93 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 83 (IMGT) or 94 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 84 (IMGT or Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iv) a VL comprising a sequence as set forth in SEQ ID NO: 149 or 153, or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(v) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 4, a CDR2 comprising a sequence set forth in SEQ ID NO: 5, and a CDR3 comprising a sequence set forth in SEQ ID NO: 6; or comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 16, a CDR2 comprising a sequence set forth in SEQ ID NO: 17 or 354, and a CDR3 comprising a sequence set forth in SEQ ID NO: 18;(vi) a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 82, a CDR2 comprising a sequence set forth in SEQ ID NO: 83 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 84; or comprising a CDR1 comprising a set forth in SEQ ID NO: 93, a CDR2 comprising a sequence set forth in SEQ ID NO: 94 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 84;(vii) a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 4, a CDR2 comprising a sequence as set forth in SEQ ID NO: 5 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 6; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 82, a CDR2 comprising a sequence as set forth in SEQ ID NO: 83 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 84; or a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 16, a CDR2 comprising a sequence as set forth in SEQ ID NO: 17 or 354 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 18; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 93, a CDR2 comprising a sequence as set forth in SEQ ID NO: 94 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 84; or(viii) a VH comprising a sequence as set forth in SEQ ID NO: 74; and a VL comprising a sequence set forth in SEQ ID NO: 149; or a VH comprising a sequence as set forth in SEQ ID NO: 78; and a VL comprising a sequence set forth in SEQ ID NO: 153.

[0058] When the CDRs are defined according to the IMGT system, the first antigen binding domain may further comprise at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 29, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 30, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%,at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 31 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 32, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 109, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 110, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 111 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 112, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0059] When the CDRs are defined according to the Kabat system, the first antigen binding domain may further comprise at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 57, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 58, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 59, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 60, or a sequence at least about 80%, at least 85%, at least90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 132, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 133, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 134, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 135, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0060] When the CDRs are defined according to the IMGT system, the first antigen binding domain may further comprise at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 45, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 46, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 47, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 48, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 113, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 114, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 115, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 116, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0061] When the CDRs are defined according to the Kabat system, the first antigen binding domain may further comprise at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 61 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 62, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 63, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 64, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 136, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 137, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ IDNO: 138, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 139, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0062] In any embodiment, the antigen binding protein comprises a variable heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 74 or 78, or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical thereto; and a variable light chain comprising the amino acid sequence as set forth in SEQ ID NO: 149 or 153; or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98 %, or at least about 99% identical thereto; wherein the variable heavy and / or light chains comprise no more than 1 , no more than 2, no more than 3, no more than 4, no more than 5, no more than 6, no more than 7, no more than 8, no more than 9, no more than 10, no more than 11 , no more than 12, no more than 13, no more than 14, no more than 15, no more than 16, no more than 17, no more than 18, no more than 19 or no more than 20 amino acid residue substitutions, deletions, or additions or combination thereof, outside the indicated CDR sequences, and wherein the antigen binding protein retains the ability to bind to CD80.

[0063] In any embodiment, the first antigen binding domain comprises:(I) a VH comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 7 (IMGT) or 19 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 8 (IMGT) or 20 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, atleast 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 9 (IMGT) or 21 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(ii) a VH comprising a sequence as set forth in SEQ ID NO: 75, or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iii) a VL comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 85 (IMGT) or 95 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 86 (IMGT) or 96 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 87 (IMGT) or 97 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iv) a VL comprising a sequence as set forth in SEQ ID NO: 150, or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(v) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 7, a CDR2 comprising a sequence set forth in SEQ ID NO: 8, and a CDR3 comprising a sequence set forth in SEQ ID NO: 9; or comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 19, a CDR2 comprising a sequence set forth in SEQ ID NO: 20, and a CDR3 comprising a sequence set forth in SEQ ID NO: 21 ; or(vi) a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 85, a CDR2 comprising a sequence set forth in SEQ ID NO: 86, and a CDR3 comprising a sequence as set forth in SEQ ID NO: 87; or comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 95, a CDR2 comprising a sequence set forth in SEQ ID NO: 96, and a CDR3 comprising a sequence set forth in SEQ ID NO: 97; or(vii) a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 7, a CDR2 comprising a sequence as set forth in SEQ ID NO: 8 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 9; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 85, a CDR2 comprising a sequence as set forth in SEQ ID NO: 86, and a CDR3 comprising a sequence as set forth in SEQ ID NO: 87; or a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 19, a CDR2 comprising a sequence as set forth in SEQ ID NO: 20 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 21 ; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 95, a CDR2 comprising a sequence as set forth in SEQ ID NO: 96, and a CDR3 comprising a sequence as set forth in SEQ ID NO: 97; or(viii) a VH comprising a sequence as set forth in SEQ ID NO: 75 and a VL comprising a sequence set forth in SEQ ID NO: 150.

[0064] When the CDRs are defined according to IMGT, the antigen binding protein may further comprise at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 33, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 34, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an aminoacid sequence of SEQ ID NO: 35, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 36, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 117, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 118, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 119, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 104, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0065] When the CDRs are defined according to Kabat, the antigen binding protein may further comprise at least one of:(I) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 65, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 66, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 67, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 68, or a sequence at least about 80%, at least85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 140, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 141 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 142, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 143, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0066] In any embodiment, the antigen binding protein comprises a variable heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 75, or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical thereto; and a variable light chain comprising the amino acid sequence as set forth in SEQ ID NO: 150; or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98 %, or at least about 99% identical thereto; wherein the variable heavy and / or light chains comprise no more than 1 , no more than 2, no more than 3, no more than 4, no more than 5, no more than 6, no more than 7, no more than 8, no more than 9, no more than 10, no more than 11 , no more than 12, no more than 13, no more than 14, no more than 15, no more than 16, no more than 17, no more than 18, no more than 19 or no more than 20 amino acid residue substitutions, deletions, or additions or combination thereof, outside the indicated CDR sequences, and wherein the antigen binding protein retains the ability to bind to CD80.

[0067] In any embodiment, the antigen binding domain comprises:(i) a VH comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 10 (IMGT) or 22 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 11 (IMGT) or 23 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 12 (IMGT) or 24 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(ii) a VH comprising a sequence as set forth in SEQ ID NO: 76, or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iii) a VL comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 88 (IMGT) or 98 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 89 (IMGT) or 99 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 90 (IMGT) or 100 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%,at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iv) a VL comprising a sequence as set forth in SEQ ID NO: 151 , or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(v) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 10, a CDR2 comprising a sequence set forth in SEQ ID NO: 11 , and a CDR3 comprising a sequence set forth in SEQ ID NO: 12; or comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 22, a CDR2 comprising a sequence set forth in SEQ ID NO: 23, and a CDR3 comprising a sequence set forth in SEQ ID NO: 24; or(vi) a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 88, a CDR2 comprising a sequence set forth in SEQ ID NO: 89, and a CDR3 comprising a sequence as set forth in SEQ ID NO: 90; or comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 98, a CDR2 comprising a sequence set forth in SEQ ID NO: 99, and a CDR3 comprising a sequence as set forth in SEQ ID NO: 100; or(vii) a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 10, a CDR2 comprising a sequence as set forth in SEQ ID NO: 11 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 12; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 88, a CDR2 comprising a sequence as set forth in SEQ ID NO: 89, and a CDR3 comprising a sequence as set forth in SEQ ID NO: 90; or a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 22, a CDR2 comprising a sequence as set forth in SEQ ID NO: 23 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 24; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 98, a CDR2 comprising a sequence as set forth in SEQ ID NO: 99, and a CDR3 comprising a sequence as set forth in SEQ ID NO: 100; or(viii) a VH comprising a sequence as set forth in SEQ ID NO: 76 and a VL comprising a sequence set forth in SEQ ID NO: 151 .

[0068] When the CDRs are defined according to IMGT, the first antigen binding protein may further comprise at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 37, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 38, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 39, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 40, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 120, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 121 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 122, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 123, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0069] When the CDRs are defined according to Kabat, the first antigen binding protein may further comprise at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 69, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 70, or a sequence at least about 80%, at least 85%, at least90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 71 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 72, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 144, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 145, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 146, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 147, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0070] In any embodiment, the antigen binding protein comprises a variable heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 76, or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical thereto; and a variable light chain comprising the amino acid sequence as set forth in SEQ ID NO: 151 ; or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98 %, or at least about 99% identical thereto; wherein the variable heavy and / or light chains comprise no more than 1 , no more than 2, no more than 3, no more than 4, no more than 5, no more than 6, no more than 7, no more than 8, no more than 9, no more than 10, no more than 11 , no morethan 12, no more than 13, no more than 14, no more than 15, no more than 16, no more than 17, no more than 18, no more than 19 or no more than 20 amino acid residue substitutions, deletions, or additions or combination thereof, outside the indicated CDR sequences, and wherein the antigen binding protein retains the ability to bind to CD80.

[0071] In any embodiment, the antigen binding domain comprises:(i) a VH comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 312 (IMGT) or 326 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 313 (IMGT) or 327 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 314 (IMGT) or 328 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(ii) a VH comprising a sequence as set forth in SEQ ID NO: 310, or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iii) a VL comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 319 (IMGT) or 333 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 320 (IMGT) or 334 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, atleast 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 321 (IMGT) or 335 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iv) a VL comprising a sequence as set forth in SEQ ID NO: 311 , or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(v) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 312, a CDR2 comprising a sequence set forth in SEQ ID NO: 313, and a CDR3 comprising a sequence set forth in SEQ ID NO: 314; or comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 326, a CDR2 comprising a sequence set forth in SEQ ID NO: 327, and a CDR3 comprising a sequence set forth in SEQ ID NO: 328;(vi) a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 319, a CDR2 comprising a sequence set forth in SEQ ID NO: 320, and a CDR3 comprising a sequence as set forth in SEQ ID NO: 321 ; or comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 333, a CDR2 comprising a sequence set forth in SEQ ID NO: 334, and a CDR3 comprising a sequence as set forth in SEQ ID NO: 335;(vii) a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 312, a CDR2 comprising a sequence as set forth in SEQ ID NO: 313 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 314; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 319, a CDR2 comprising a sequence as set forth in SEQ ID NO: 320, and a CDR3 comprising a sequence as set forth in SEQ ID NO: 321 ; or a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 326, a CDR2 comprising a sequence as set forth in SEQ ID NO: 327 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 328; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 333, a CDR2 comprising a sequenceas set forth in SEQ ID NO: 334, and a CDR3 comprising a sequence as set forth in SEQ ID NO: 335; or(viii) a VH comprising a sequence as set forth in SEQ ID NO: 310 and a VL comprising a sequence set forth in SEQ ID NO: 311 .

[0072] When the CDRs are defined according to IMGT, the first antigen binding protein may further comprise at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 315, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 316, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 317, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 318, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 322, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 323, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 324, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 325, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0073] When the CDRs are defined according to Kabat, the first antigen binding protein may further comprise at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 329, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 330, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 331 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 332, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 336, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 337, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 338, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 339, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0074] In any embodiment, the antigen binding protein comprises a variable heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 310, or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical thereto; anda variable light chain comprising the amino acid sequence as set forth in SEQ ID NO: 31 1 ; or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98 %, or at least about 99% identical thereto; wherein the variable heavy and / or light chains comprise no more than 1 , no more than 2, no more than 3, no more than 4, no more than 5, no more than 6, no more than 7, no more than 8, no more than 9, no more than 10, no more than 11 , no more than 12, no more than 13, no more than 14, no more than 15, no more than 16, no more than 17, no more than 18, no more than 19 or no more than 20 amino acid residue substitutions, deletions, or additions or combination thereof, outside the indicated CDR sequences, and wherein the antigen binding protein retains the ability to bind to CD80.

[0075] In any embodiment, the second polypeptide for binding to CD80 is in the form of a native binding partner of CD80, or a functional homologue or derivative thereof, that preferably inhibits the binding of CD28 to CD80.

[0076] As used herein, a functional homologue or derivative of a native binding partner of CD80 refers to a homologue or variant having about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% amino acid identity or similarity to the amino acid sequence of the naturally occurring native binding partner, and that retains the ability to bind to CD80. Similarly a variant of a native binding partner of CD80 retains the ability to bind to CD80 despite any modification or variant of the native polypeptide (including posttranslational modifications, non-natural amino acid residues and the like).

[0077] In one example, the native binding partner of CD80 is CTLA4 and the second polypeptide for binding to CD80 therefore comprises the sequence of a CTLA4 protein. The CTLA4 protein sequence may be derived from the soluble isoform of the protein, or transmembrane isoform.

[0078] Examples of the amino acid sequence of a CTLA4 protein sequence are set forth herein in any of SEQ ID NOs: 304 to 309, 341 and 342.

[0079] The CTLA4 protein sequence may be derived from the soluble isoform of CTLA4, or the transmembrane isoform of CTLA4 with deletions / substitutions in the homodimer interface region to prevent potential homodimerisation / aggregation.

[0080] In certain embodiments, the CTLA4 protein sequence may be fused or joined directly, or via a linker, to the first antigen binding protein of the bispecific molecule. Optionally, the C terminal region of the CTLA4 protein is joined (eg via a linker) to the N terminal region of the first antigen binding protein. The first antigen binding protein may be in the form of any suitable antigen binding protein, such as an immunoglobulin variable domain, antibody, dab, scFv, Fab, Fab', F(ab')2, Fv fragment, diabody, triabody, linear antibody, single-chain antibody molecule, or multispecific antibody.

[0081] In certain non-limiting examples, the CTLA4 protein may be joined, directly or via a linker, to an antigen binding protein comprising the sequence of any of the B5, 19B10, 2B29, 2B30 or TKMF5 proteins as described herein, including wherein the B5, 19B10, 2B29, 2B30 or TKMF5 proteins are in the form of an immunoglobulin variable domain, antibody, dab, scFv, Fab, Fab', F(ab')2, Fv fragment, diabody, triabody, linear antibody, single-chain antibody molecule, or multispecific antibody.

[0082] In alternative embodiments, the CTLA4 protein sequence may be provided in the form of a fusion protein, such as when joined to an Fc region of an antibody or any other moiety for stabilising the CTLA4 protein. The CTLA4 protein sequence may be directly joined to an Fc region of an antibody, or may be joined via a linker. Accordingly, in further embodiments, the bispecific molecule comprises a CTLA4-fusion protein joined directly, or via a linker, to a first antigen binding protein for inhibiting the binding of PD-L1 to CD80. The first antigen binding protein may be in the form of any suitable antigen binding protein, such as an immunoglobulin variable domain, antibody, dab, scFv, Fab, Fab', F(ab')2, Fv fragment, diabody, triabody, linear antibody, single-chain antibody molecule, or multispecific antibody.

[0083] In certain non-limiting examples, the CTLA4-fusion protein may be joined, directly or via a linker, to an antigen binding protein comprising the sequence of any of the B5, 19B10, 2B29, 2B30 or TKMF5 proteins as described herein, including wherein the B5, 19B10, 2B29, 2B30 or TKMF5 proteins are in the form of an immunoglobulin variable domain, antibody, dab, scFv, Fab, Fab', F(ab')2, Fv fragment, diabody, triabody, linear antibody, single-chain antibody molecule, or multispecific antibody.

[0084] In any embodiment, the second polypeptide for binding to CD80 is in the form of an antigen binding domain and comprises:FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4, andFR1 a - CDR1 a - FR2a - CDR2a - FR3a - CDR3a - FR4a, wherein:FR1 , FR2, FR3 and FR4 are each framework regions;CDR1 , CDR2 and CDR3 are each complementarity determining regions;FR1 a, FR2a, FR3a and FR4a are each framework regions;CDR1 a, CDR2a and CDR3a are each complementarity determining regions; wherein the sequence of any of the framework regions or complementarity determining regions are as described herein, preferably as described in Tables 7 to 12 herein.

[0085] In any embodiment, CDR1 , CDR2 and CDR3 refer to complementarity determining regions from the variable heavy chain of an antibody (a VH), CDR1a, CDR2a and CDR3a are complementarity determining regions from the variable light chain of an antibody (a VL), or where CDR1 , CDR2 and CDR3 are complementarity determining regions from the VL, CDR1a, CDR2a and CDR3a are complementarity determining regions from VH. In such examples, the CDRs may be referred to as CDRH1 , CDRH2, CDRH3, CDRL1 , CDRL2 and CDRL3 as the case may be.

[0086] In preferred embodiments, the second polypeptide, in the form of an antigen binding protein, and that inhibits the binding of CD28 to CD80 is capable of binding to or specifically binding to residues of the membrane distal IgV domain of human CD80 (corresponding to residues G34 to A140 of human CD80). Optionally, the second antigen binding protein as described herein does not bind to the region or portion of CD80 that is bound by CD28, but upon binding to CD80, prevents or reduces the binding of CD28 to CD80.

[0087] In preferred embodiments, the second antigen binding protein as described herein is capable of binding to or specifically binding to the region or portion of CD80 that is bound by CD28.

[0088] In certain embodiments, upon binding to CD80, the second antigen binding protein does not inhibit the binding of PD-L1 to CD80.

[0089] In any embodiment, the second antigen binding protein for binding to CD80:- comprises a VH comprising a sequence as set forth in SEQ ID NO: 230 and a VL comprising a sequence as set forth in SEQ ID NO: 297;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 231 and a VL comprising a sequence as set forth in SEQ ID NO: 298;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 232, and a VL comprising a sequence as set forth in SEQ ID NO: 299;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 233, and a VL comprising a sequence as set forth in SEQ ID NO: 300;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 234, and a VL comprising a sequence as set forth in SEQ ID NO: 301 ;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 235, and a VL comprising a sequence as set forth in SEQ ID NO: 302; or- comprises a VH comprising a sequence as set forth in SEQ ID NO: 236, and a VL comprising a sequence as set forth in SEQ ID NO: 303.

[0090] In any embodiment, the second antigen binding protein comprises a CDRH1 , a CDRH2 and / or a CDRH3 of an antigen binding domain having a variable heavy chain as defined in any one of SEQ ID NOs: 230, 231 , 232, 233, 234, 235 or 236.

[0091] In any embodiment, the second antigen binding protein comprises a CDRL1 , a CDRL2 and / or a CDRL3 of an antigen binding domain having a variable light chain as defined in any one of SEQ ID NOs: 297, 298, 299, 300, 301 , 302 or 303.

[0092] In any embodiment, the second antigen binding protein comprises:- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 230, and a CDR1 , a CDR2 and a CDR3 ofan antigen binding domain having a variable light chain as defined in SEQ ID NO: 297;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 231 , and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 298;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 232, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 299;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 233, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 300;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 234, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 301 ;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 235, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 302; or- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 236, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 303.

[0093] In any embodiment, the second antigen binding protein described herein comprises:FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4 - linker - FR1 a - CDR1 a - FR2a - CDR2a - FR3a - CDR3a - FR4a.

[0094] As defined herein, the linker may be a chemical, one or more amino acids, or a disulphide bond formed between two cysteine residues.

[0095] In certain preferred embodiments, the second antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of (in order of N to C terminus or C to N terminus) SEQ ID NOs: 230 and 297.

[0096] In certain preferred embodiments, the second antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of (in order of N to C terminus or C to N terminus) SEQ ID NOs: 231 and 298.

[0097] In certain preferred embodiments, the second antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of (in order of N to C terminus or C to N terminus) SEQ ID NOs: 232 and 299.

[0098] In certain preferred embodiments, the second antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of (in order of N to C terminus or C to N terminus) SEQ ID NOs: 233 and 300.

[0099] In certain preferred embodiments, the second antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of (in order of N to C terminus or C to N terminus) SEQ ID NOs: 234 and 301 .

[0100] In certain preferred embodiments, the second antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of (in order of N to C terminus or C to N terminus) SEQ ID NOs: 235 and 302.

[0101] In certain preferred embodiments, the second antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of (in order of N to C terminus or C to N terminus) SEQ ID NOs: 236 and 303.

[0102] In a particularly preferred embodiment, the second antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of, in order N to C terminus, SEQ ID NO: 297 and SEQ ID NO: 230 (ie VL to VH). Optionally the antigen binding protein comprises SEQ ID NO: 297 (VL) - linker - SEQ ID NO: 230 (VH).

[0103] In a particularly preferred embodiment, the second antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of, in order Nto C terminus, SEQ ID NO: 298 and SEQ ID NO: 231 (ie VL to VH). Optionally the antigen binding protein comprises SEQ ID NO: 298 (VL) - linker - SEQ ID NO: 231 (VH).

[0104] In a particularly preferred embodiment, the second antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of, in order N to C terminus, SEQ ID NO: 299 and SEQ ID NO: 232 (ie VL to VH), optionally SEQ ID NO: 299 (VL) - linker - SEQ ID NO: 232 (VH).

[0105] In a particularly preferred embodiment, the second antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of, in order N to C terminus, SEQ ID NO: 300 and SEQ ID NO: 233 (ie VL to VH), optionally SEQ ID NO: 300 (VL) - linker - SEQ ID NO: 233 (VH).

[0106] In a particularly preferred embodiment, the second antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of, in order N to C terminus, SEQ ID NO: 301 and SEQ ID NO: 234 (ie VL to VH), optionally SEQ ID NO: 301 (VL) - linker - SEQ ID NO: 234 (VH).

[0107] In a particularly preferred embodiment, the second antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of, in order N to C terminus, SEQ ID NO: 302 and SEQ ID NO: 235 (ie VL to VH), optionally SEQ ID NO: 302 (VL) - linker - SEQ ID NO: 235 (VH).

[0108] In a particularly preferred embodiment, the second antigen binding protein comprises, consists essentially of or consists of the amino acid sequence of, in order N to C terminus, SEQ ID NO: 303 and SEQ ID NO: 236 (ie VL to VH), optionally SEQ ID NO: 303 (VL) - linker - SEQ ID NO: 236 (VH).

[0109] In any embodiment, the second antigen binding protein comprises:(i) a VH comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 154 (IMGT) or 166 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 155 (IMGT) or 167 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, atleast 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 156 (IMGT) or 168 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(ii) a VH comprising a sequence as set forth in SEQ ID NO: 230, or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iii) a VL comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 237 (IMGT) or 246 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 238 (IMGT) or 247 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 239 (IMGT) or 248 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iv) a VL comprising a sequence as set forth in SEQ ID NO: 297, or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(v) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 154, a CDR2 comprising a sequence set forth in SEQ ID NO: 155, and a CDR3 comprising a sequence set forth in SEQ ID NO: 156; or comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 166, a CDR2 comprising a sequence set forth in SEQ ID NO: 167, and a CDR3 comprising a sequence set forth in SEQ ID NO: 168;(vi) a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 237, a CDR2 comprising a sequence set forth in SEQ ID NO: 238 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 239; or comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 246, a CDR2 comprising a sequence set forth in SEQ ID NO: 247, and a CDR3 comprising a sequence set forth in SEQ ID NO: 248;(vii) a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 154, a CDR2 comprising a sequence as set forth in SEQ ID NO: 155 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 156; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 237, a CDR2 comprising a sequence as set forth in SEQ ID NO: 238 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 239; or a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 166, a CDR2 comprising a sequence as set forth in SEQ ID NO: 167 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 168; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 246, a CDR2 comprising a sequence as set forth in SEQ ID NO: 237 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 248; or(viii) a VH comprising a sequence as set forth in SEQ ID NO: 230 and a VL comprising a sequence set forth in SEQ ID NO: 297.

[0110] When the CDRs are defined according to IMGT, the second antigen binding domain may further comprise at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 181 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 340, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%,at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 182, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 183, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 259, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 260, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 261 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 262, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0111] When the CDRs are defined according to Kabat, the second antigen binding domain may further comprise at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 203, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 204, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 205, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 206, or a sequence at least about 80%, at least85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 280, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 283, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 281 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 262, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0112] In any embodiment, the second antigen binding protein comprises a variable heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 230, or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical thereto; and a variable light chain comprising the amino acid sequence as set forth in SEQ ID NO: 297; or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98 %, or at least about 99% identical thereto; wherein the variable heavy and / or light chains comprise no more than 1 , no more than 2, no more than 3, no more than 4, no more than 5, no more than 6, no more than 7, no more than 8, no more than 9, no more than 10, no more than 11 , no more than 12, no more than 13, no more than 14, no more than 15, no more than 16, no more than 17, no more than 18, no more than 19 or no more than 20 amino acid residue substitutions, deletions, or additions or combination thereof, outside the indicated CDR sequences, and wherein the antigen binding protein retains the ability to bind to CD80.

[0113] In any embodiment, second antigen binding domain comprises:(i) a VH comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 154 (IMGT) or 169 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 155 (IMGT) or 170 or 356 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 156 (IMGT) or 171 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(ii) a VH comprising a sequence as set forth in SEQ ID NO: 231 or 235, or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iii) a VL comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 237 (IMGT) or 249 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 238 (IMGT) or 250 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 239 (IMGT) or 251 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iv) a VL comprising a sequence as set forth in SEQ ID NO: 298 or 302, or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(v) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 154, a CDR2 comprising a sequence set forth in SEQ ID NO: 155, and a CDR3 comprising a sequence set forth in SEQ ID NO: 156; or comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 169, a CDR2 comprising a sequence set forth in SEQ ID NO: 170 or 356, and a CDR3 comprising a sequence set forth in SEQ ID NO: 171 ;(vi) a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 237, a CDR2 comprising a sequence set forth in SEQ ID NO: 238 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 239; or comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 249, a CDR2 comprising a sequence set forth in SEQ ID NO: 250 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 251 ;(vii) a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 154, a CDR2 comprising a sequence as set forth in SEQ ID NO: 155 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 156; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 237, a CDR2 comprising a sequence as set forth in SEQ ID NO: 238 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 239; or VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 169, a CDR2 comprising a sequence as set forth in SEQ ID NO: 170 or 356 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 171 ; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 249, a CDR2 comprising a sequence as set forth in SEQ ID NO: 250 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 251 ; or(viii) a VH comprising a sequence as set forth in SEQ ID NO: 231 and a VL comprising a sequence set forth in SEQ ID NO: 298; or a VH comprising a sequence asset forth in SEQ ID NO: 235 and a VL comprising a sequence set forth in SEQ ID NO: 302.

[0114] When the CDRs are defined according to IMGT, the second antigen binding domain may further comprise at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 184, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 340, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 185, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 183, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 263, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 260, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 264, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 262, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0115] When the CDRs are defined according to Kabat, the second antigen binding domain may further comprise at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 207, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 208, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 209, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 210, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 282, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 283, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 284, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 262, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0116] The second antigen binding domain may further comprise at least one of:(I) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 196, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 197, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%,at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 198, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 199, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 274, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 275, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 276, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 262, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0117] The second antigen binding domain may further comprise at least one of:(I) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 223, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 224, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 225, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 226, or a sequence at least about 80%, at least85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 292, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 293, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 294, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 262, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0118] In any embodiment, the second antigen binding protein comprises a variable heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 231 , or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical thereto; and a variable light chain comprising the amino acid sequence as set forth in SEQ ID NO: 298; or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98 %, or at least about 99% identical thereto; wherein the variable heavy and / or light chains comprise no more than 1 , no more than 2, no more than 3, no more than 4, no more than 5, no more than 6, no more than 7, no more than 8, no more than 9, no more than 10, no more than 11 , no more than 12, no more than 13, no more than 14, no more than 15, no more than 16, no more than 17, no more than 18, no more than 19 or no more than 20 amino acid residue substitutions, deletions, or additions or combination thereof, outside the indicated CDR sequences, and wherein the antigen binding protein retains the ability to bind to CD80.

[0119] In any embodiment, the second antigen binding protein comprises a variable heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 235, or asequence at least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical thereto; and a variable light chain comprising the amino acid sequence as set forth in SEQ ID NO: 302; or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98 %, or at least about 99% identical thereto; wherein the variable heavy and / or light chains comprise no more than 1 , no more than 2, no more than 3, no more than 4, no more than 5, no more than 6, no more than 7, no more than 8, no more than 9, no more than 10, no more than 11 , no more than 12, no more than 13, no more than 14, no more than 15, no more than 16, no more than 17, no more than 18, no more than 19 or no more than 20 amino acid residue substitutions, deletions, or additions or combination thereof, outside the indicated CDR sequences, and wherein the antigen binding protein retains the ability to bind to CD80.

[0120] In any embodiment, the second antigen binding domain comprises:(i) a VH comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 158 (IMGT) or 172 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO:159 (IMGT) or 173 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 160 (IMGT) or 174 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(ii) a VH comprising a sequence as set forth in SEQ ID NO: 232, or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%,at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iii) a VL comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 240 (IMGT) or 252 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 241 (IMGT) or 253 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 242 (IMGT) or 254 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iv) a VL comprising a sequence as set forth in SEQ ID NO: 299, or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(v) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 158, a CDR2 comprising a sequence set forth in SEQ ID NO: 159, and a CDR3 comprising a sequence set forth in SEQ ID NO: 160; or comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 172, a CDR2 comprising a sequence set forth in SEQ ID NO:173, and a CDR3 comprising a sequence set forth in SEQ ID NO: 174;(vi) a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 240, a CDR2 comprising a sequence set forth in SEQ ID NO: 241 , and a CDR3 comprising a sequence as set forth in SEQ ID NO: 242; or comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 252, a CDR2 comprising a sequence set forth in SEQ ID NO: 253, and a CDR3 comprising a sequence set forth in SEQ ID NO: 254;(vi i) a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 158, a CDR2 comprising a sequence as set forth in SEQ ID NO: 159 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 160; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 240, a CDR2 comprising a sequence as set forth in SEQ ID NO: 241 , and a CDR3 comprising a sequence as set forth in SEQ ID NO: 242; or a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 172, a CDR2 comprising a sequence as set forth in SEQ ID NO: 173 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 174; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 252, a CDR2 comprising a sequence as set forth in SEQ ID NO: 253, and a CDR3 comprising a sequence as set forth in SEQ ID NO: 254; or(viii) a VH comprising a sequence as set forth in SEQ ID NO: 232 and a VL comprising a sequence set forth in SEQ ID NO: 299.

[0121] When the CDRS are defined by IMGT, the antigen binding protein may further comprise at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 186, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 187, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 188, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 183, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 265, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO:266, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 267, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 268, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0122] When the CDRs are defined by Kabat, the antigen binding protein may further comprise at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 21 1 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 212, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 213, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 214, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 285, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 286, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 287, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%,at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 288, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0123] In any embodiment, the antigen binding protein comprises a variable heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 232, or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical thereto; and a variable light chain comprising the amino acid sequence as set forth in SEQ ID NO: 299; or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98 %, or at least about 99% identical thereto; wherein the variable heavy and / or light chains comprise no more than 1 , no more than 2, no more than 3, no more than 4, no more than 5, no more than 6, no more than 7, no more than 8, no more than 9, no more than 10, no more than 11 , no more than 12, no more than 13, no more than 14, no more than 15, no more than 16, no more than 17, no more than 18, no more than 19 or no more than 20 amino acid residue substitutions, deletions, or additions or combination thereof, outside the indicated CDR sequences, and wherein the antigen binding protein retains the ability to bind to CD80.

[0124] In any embodiment, the second antigen binding domain comprises:(i) a VH comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 355 (IMGT) or 175 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 161 (IMGT) or 176 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 162 (IMGT) or 177 (Kabat), or asequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(ii) a VH comprising a sequence as set forth in SEQ ID NO: 233, or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iii) a VL comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 240 (IMGT) or 255 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 243 (IMGT) or 256 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 244 (IMGT) or 257 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iv) a VL comprising a sequence as set forth in SEQ ID NO: 300, or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(v) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 355, a CDR2 comprising a sequence set forth in SEQ ID NO: 161 , and a CDR3 comprising a sequence set forth in SEQ ID NO: 162; or comprising a CDR1 comprising a sequenceset forth in SEQ ID NO: 175, a CDR2 comprising a sequence set forth in SEQ ID NO: 176, and a CDR3 comprising a sequence set forth in SEQ ID NO: 177;(vi) a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 240, a CDR2 comprising a sequence set forth in SEQ ID NO: 243, and a CDR3 comprising a sequence as set forth in SEQ ID NO: 244; or comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 255, a CDR2 comprising a sequence set forth in SEQ ID NO: 256, and a CDR3 comprising a sequence set forth in SEQ ID NO: 257(vii) a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 355, a CDR2 comprising a sequence as set forth in SEQ ID NO: 161 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 162; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 240, a CDR2 comprising a sequence as set forth in SEQ ID NO: 243, and a CDR3 comprising a sequence as set forth in SEQ ID NO: 244; or a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 175, a CDR2 comprising a sequence as set forth in SEQ ID NO: 176 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 177 and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 255, a CDR2 comprising a sequence as set forth in SEQ ID NO: 256, and a CDR3 comprising a sequence as set forth in SEQ ID NO: 257; or(viii) a VH comprising a sequence as set forth in SEQ ID NO: 233 and a VL comprising a sequence set forth in SEQ ID NO: 300.

[0125] When the CDRs are defined according to IMGT, the second antigen binding protein may further comprise at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 189, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 190, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 191 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 192, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 265, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 269, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 270, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 271 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0126] When the CDRs are defined according to Kabat, the second antigen binding protein may further comprise at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 215, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 216, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 217, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 218, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 285, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 289, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 290, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 271 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0127] In any embodiment, the antigen binding protein comprises a variable heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 233, or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical thereto; and a variable light chain comprising the amino acid sequence as set forth in SEQ ID NO: 300; or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98 %, or at least about 99% identical thereto; wherein the variable heavy and / or light chains comprise no more than 1 , no more than 2, no more than 3, no more than 4, no more than 5, no more than 6, no more than 7, no more than 8, no more than 9, no more than 10, no more than 11 , no more than 12, no more than 13, no more than 14, no more than 15, no more than 16, no more than 17, no more than 18, no more than 19 or no more than 20 amino acid residue substitutions, deletions, or additions or combination thereof, outside the indicated CDR sequences, and wherein the antigen binding protein retains the ability to bind to CD80.

[0128] In any embodiment, the second antigen binding domain comprises:(i) a VH comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 163 (IMGT) or 178 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%,at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 164 (IMGT) or 179 or 357 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 165 (IMGT) or 180 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(ii) a VH comprising a sequence as set forth in SEQ ID NO: 234 or 236, or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iii) a VL comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 245 (IMGT) or 258 or 358 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 243 (IMGT) or 256 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 244 (IMGT) or 257 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iv) a VL comprising a sequence as set forth in SEQ ID NO: 301 or 303, or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(v) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 163, a CDR2 comprising a sequence set forth in SEQ ID NO: 164, and a CDR3 comprising a sequence set forth in SEQ ID NO: 165; or comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 178, a CDR2 comprising a sequence set forth in SEQ ID NO:179 or 357, and a CDR3 comprising a sequence set forth in SEQ ID NO: 180;(vi) a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 245; a CDR2 comprising a sequence set forth in SEQ ID NO: 243, and a CDR3 comprising a sequence as set forth in SEQ ID NO: 244; or comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 258 or 358; a CDR2 comprising a sequence set forth in SEQ ID NO: 256, and a CDR3 comprising a sequence as set forth in SEQ ID NO: 257;(vii) a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 163, a CDR2 comprising a sequence as set forth in SEQ ID NO: 164 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 165; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 245, a CDR2 comprising a sequence as set forth in SEQ ID NO: 243, and a CDR3 comprising a sequence as set forth in SEQ ID NO: 244; or a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO:178, a CDR2 comprising a sequence as set forth in SEQ ID NO: 179 or 357 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 180; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 258 or 358, a CDR2 comprising a sequence as set forth in SEQ ID NO: 256, and a CDR3 comprising a sequence as set forth in SEQ ID NO: 257; or(viii) a VH comprising a sequence as set forth in SEQ ID NO: 234 and a VL comprising a sequence set forth in SEQ ID NO: 301 ; or a VH comprising a sequence as set forth in SEQ ID NO: 236 and a VL comprising a sequence set forth in SEQ ID NO: 303.

[0129] When the CDRs are defined according to IMGT, the second antigen binding protein may further comprise at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 193, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 190, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 194, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 195, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 265, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 272, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 270, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 273, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0130] When the CDRs are defined according to Kabat, the second antigen binding protein may further comprise at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 219, or a sequence at least about 80%, at least 85%, at least 90%, atleast 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 220, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 221 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 222, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 285, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 291 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 290, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 273, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0131] When the CDRs are defined according to IMGT, the second antigen binding protein may further comprise at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 200, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 201 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an aminoacid sequence of SEQ ID NO: 202, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 199, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 277, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 272, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 278, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 279, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0132] When the CDRs are defined according to Kabat, the second antigen binding protein may further comprise at least one of:(I) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 227, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 228, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 229, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 226, or a sequence at least about 80%, at least85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 295, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 291 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 296, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 279, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

[0133] In any embodiment, the antigen binding protein comprises a variable heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 234, or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical thereto; and a variable light chain comprising the amino acid sequence as set forth in SEQ ID NO: 301 ; or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98 %, or at least about 99% identical thereto; wherein the variable heavy and / or light chains comprise no more than 1 , no more than 2, no more than 3, no more than 4, no more than 5, no more than 6, no more than 7, no more than 8, no more than 9, no more than 10, no more than 11 , no more than 12, no more than 13, no more than 14, no more than 15, no more than 16, no more than 17, no more than 18, no more than 19 or no more than 20 amino acid residue substitutions, deletions, or additions or combination thereof, outside the indicated CDR sequences, and wherein the antigen binding protein retains the ability to bind to CD80.

[0134] In any embodiment, the antigen binding protein comprises a variable heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 236, or a sequence atleast about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical thereto; and a variable light chain comprising the amino acid sequence as set forth in SEQ ID NO: 303; or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98 %, or at least about 99% identical thereto; wherein the variable heavy and / or light chains comprise no more than 1 , no more than 2, no more than 3, no more than 4, no more than 5, no more than 6, no more than 7, no more than 8, no more than 9, no more than 10, no more than 11 , no more than 12, no more than 13, no more than 14, no more than 15, no more than 16, no more than 17, no more than 18, no more than 19 or no more than 20 amino acid residue substitutions, deletions, or additions or combination thereof, outside the indicated CDR sequences, and wherein the antigen binding protein retains the ability to bind to CD80.

[0135] As described herein, an antigen binding protein may be in the form of:(i) a single domain antibody (sdAb);(ii) a single chain Fv fragment (scFv);(iii) a dimeric scFv (di-scFv); or(iv) one of (i) or (iii) linked to a constant region of an antibody, Fc or a heavy chain constant domain (CH) 2 and / or CH3.

[0136] Further, as described herein, an antigen binding protein may be in the form of:(i) a diabody;(ii) a triabody;(iii) a tetrabody;(iv) a Fab;(v) a F(ab’)2;(vi) a Fv;(vii) a bispecific antibody or other form of multispecific antibody (including a BiTE); or(viii) one of (i) to (vii) linked to a constant region of an antibody, Fc or a heavy chain constant domain (CH) 2 and / or CH3.

[0137] The foregoing antigen binding proteins can also be referred to as antigen binding domains of antibodies.

[0138] Preferably, an antigen binding protein as described herein is an antibody or antigen binding fragment thereof. Typically, the antigen binding protein is an antibody, for example, a monoclonal antibody. The antigen binding protein may be in the form of a recombinant or modified antibody (e.g., chimeric antibody, humanised antibody, human antibody, CDR-grafted antibody, primatised antibody, de-immunised antibody, synhumanised antibody, half-antibody, bispecific antibody, trispecific antibody or multispecific antibody). The antibody may further comprise a chemical modification, such as conjugation to an active agent or radiolabel, or an agent for improving solubility or other modification described herein

[0139] As used herein the antigen binding protein may be a variable domain.

[0140] As used herein, the complementarity determining region sequences (CDRs) of an antigen binding protein of the invention may be defined according to the IMGT, Chothia or Kabat numbering systems, or any other CDR numbering system known to the skilled person or described herein.

[0141] In any embodiment, an antigen binding protein as described herein wherein an amino acid sequence forming one or more of FR1 , CDR1 , FR2, CDR2, FR3, CDR3 and FR4 is a human sequence.

[0142] An antigen binding protein as described herein may comprise a human constant region, e.g., an IgG constant region, such as an IgGi, IgGa, IgGa or lgG4 constant region or mixtures thereof. In the case of an antibody or protein comprising a VH and a VL, the VH can be linked to a heavy chain constant region and the VL can be linked to a light chain constant region.

[0143] In one example, an antigen binding protein as described herein comprises a constant region of an IgGi antibody or a stabilised constant region of an IgGi antibody.In one example, the protein or antibody comprises an IgG 1 constant region with a proline at position 241 (according to the numbering system of Kabat (Kabat et al., Sequences of Proteins of Immunological Interest Washington DC United States Department of Health and Human Services, 1987 and / or 1991 )).

[0144] In one example, an antigen binding protein as described herein or a composition of an antigen binding protein as described herein, comprises a heavy chain constant region, comprising a stabilised heavy chain constant region, comprising a mixture of sequences fully or partially with or without the C-terminal lysine residue.

[0145] In one example, an antigen binding protein comprises a VH disclosed herein linked or fused to an IgGi constant region or stabilised IgGi constant region (e.g., as discussed above) and the VL is linked to or fused to a kappa light chain constant region.

[0146] In any aspect of the present invention, the antibody is a naked antibody. Specifically, the antibody is in a non-conjugated form and is not adapted to form a conjugate.

[0147] The invention provides a fusion protein comprising an antigen binding protein, immunoglobulin variable domain, antibody, dab, scFv, Fab, Fab', F(ab')2, Fv fragment, diabody, triabody, linear antibody, single-chain antibody molecule, or multispecific antibody as described herein.

[0148] The invention also provides a conjugate in the form of an antigen binding protein, immunoglobulin variable domain, antibody, dab, scFv, Fab, Fab', F(ab')2, Fv fragment, diabody, triabody, linear antibody, single-chain antibody molecule, or multispecific antibody or fusion protein as described herein, conjugated to a label or a cytotoxic agent. The cytotoxic agent may be a chemotherapeutic agent or other agent used for the treatment of a disease.

[0149] In another embodiment, the antigen binding protein comprises an Fc region that is engineered to:- increase the in vitro or in vivo half-life;- have an increased capacity to induce antibody-dependent cell mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) or complement-dependent cytotoxicity;- reduce effector function; or- increase co-engagement of the antigen binding protein.

[0150] Mutations, deletions or modifications of amino acids in the Fc region which affect half-life, ADCC, ADCP or complement-dependent cytotoxicity, effector function are known to the skilled person and further described herein.

[0151] The functional characteristics of an antigen binding protein of the invention will be taken to apply mutatis mutandis to an antibody of the invention.

[0152] In any aspect of the invention and in any antigen binding protein described herein, there further includes an Fc region that is engineered to have reduced capacity to induce antibody-dependent cell-mediated cytotoxicity (ADCC). Preferably, the reduced capacity to induce ADCC is conferred by mutation, deletion or modification of amino acids in the Fc region which interact with an Fc receptor.Examples of particular bispecific / biparatopic architectures

[0153] It will be appreciated that the specific architecture of the bispecific molecules of the invention are adaptable.

[0154] For example, the architecture of the molecule may comprise:- a first polypeptide, being an antigen binding protein for binding to CD80 and for inhibiting the binding of PD-L1 to CD80, joined to a CTLA4-Fc fusion protein; or- a first polypeptide, being an antigen binding protein for binding to CD80 and for inhibiting the binding of PD-L1 to CD80, joined to a second antigen binding protein for binding to CD80 and for inhibiting the binding of CD28 to CD80.

[0155] It will be appreciated that the antigen binding protein to which the CD80 native binding partner is joined, may be in any antigen binding format as described herein, such as an scFv, a di-scFv, a Fab, a F(ab’)2, or an IgG.

[0156] In certain preferred embodiments, the bispecific molecule may comprise i) CTLA4 fused to an Fc region of an antibody, joined to an scFv, (or an scFc-Fc fusion) as herein described, for binding to CD80 and for directly inhibiting the binding of PD-L1 to CD80.

[0157] In an embodiment where the second polypeptide of the bispecific molecule is an antigen-binding domain for binding to CD80 and for inhibting the binding of CD28 thereto, the architecture of the molecule may comprise:- a first polypeptide, comprising an antigen binding protein for binding to CD80 and for inhibiting the binding of PD-L1 to CD80; and- a second polypeptide, comprising an antigen binding protein for binding to CD80 and for inhibiting the binding of PD-L1 to CD80, wherein the antigen binding proteins may be in any antigen binding format as described herein, such as an scFv, a di-scFv, a Fab, a F(ab’)2, or an IgG.

[0158] For example, the first and second polypeptides may each be or may individually be in the form of an scFv or any other antigen binding fragment of an antibody. The scFvs may be in the arrangement, N to C terminus: VH to VL (so-called “HL” format) or VL to VH (so-called “LH” format), and optionally wherein the VL and VH regions (such as defined herein in the tables) are joined via a linker region.

[0159] The skilled person will be familiar with typical linker regions for linking VL and VH regions from an antigen binding domains, and such linker regions are further described herein.

[0160] In any embodiment, the first antigen binding protein for binding to CD80 comprises:- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 73, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 148;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 74, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 149;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 75, and a CDR1 , a CDR2 and a CDR3 ofan antigen binding domain having a variable light chain as defined in SEQ ID NO: 150;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 76, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 151 ;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 77, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 152;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 78, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 153; or- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 310 and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 311. and the second antigen binding protein for binding to CD80 comprises:- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 230, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 297;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 231 , and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 298;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 232, and a CDR1 , a CDR2 and a CDR3 ofan antigen binding domain having a variable light chain as defined in SEQ ID NO: 299;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 233, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 300;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 234, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 301 ;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 235, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 302; or- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 236, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 303.

[0161] In any embodiment, the first antigen binding protein for binding to CD80 comprises:- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 73, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 148;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 74, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 149;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 75, and a CDR1 , a CDR2 and a CDR3 ofan antigen binding domain having a variable light chain as defined in SEQ ID NO: 150;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 76, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 151 ;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 77, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 152;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 78, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 153; or- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 310 and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 311. and the second protein for binding to CD80 comprises the sequence of a CTLA4 protein, wherein the CTLA4 protein sequence may be derived from the soluble isoform of the protein, or transmembrane isoform (and may include an amino acid sequence as set forth in any of SEQ ID NOs: 304 to 309, 341 and 342, or CD80-binding variants thereof.

[0162] In any embodiment, the first antigen binding protein for binding to CD80:- comprises a VH comprising a sequence as set forth in SEQ ID NO: 73 and a VL comprising a sequence as set forth in SEQ ID NO: 148;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 77 and a VL comprising a sequence as set forth in SEQ ID NO: 152;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 74 and a VL comprising a sequence as set forth in SEQ ID NO: 149;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 78 and a VL comprising a sequence as set forth in SEQ ID NO: 153;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 75, and a VL comprising a sequence as set forth in SEQ ID NO: 150;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 76, and a VL comprising a sequence as set forth in SEQ ID NO: 151 ; or- comprises a VH comprising a sequence as set forth in SEQ ID NO: 310, and a VL comprising a sequence as set forth in SEQ ID NO: 311 ; and wherein the second antigen binding protein:- comprises a VH comprising a sequence as set forth in SEQ ID NO: 230 and a VL comprising a sequence as set forth in SEQ ID NO: 297;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 231 and a VL comprising a sequence as set forth in SEQ ID NO: 298;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 232, and a VL comprising a sequence as set forth in SEQ ID NO: 299;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 233, and a VL comprising a sequence as set forth in SEQ ID NO: 300;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 234, and a VL comprising a sequence as set forth in SEQ ID NO: 301 ;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 235, and a VL comprising a sequence as set forth in SEQ ID NO: 302; or- comprises a VH comprising a sequence as set forth in SEQ ID NO: 236, and a VL comprising a sequence as set forth in SEQ ID NO: 303.

[0163] In any embodiment, the first antigen binding protein for binding to CD80:- comprises a VH comprising a sequence as set forth in SEQ ID NO: 73 and a VL comprising a sequence as set forth in SEQ ID NO: 148;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 77 and a VL comprising a sequence as set forth in SEQ ID NO: 152;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 74 and a VL comprising a sequence as set forth in SEQ ID NO: 149;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 78 and a VL comprising a sequence as set forth in SEQ ID NO: 153;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 75, and a VL comprising a sequence as set forth in SEQ ID NO: 150;- comprises a VH comprising a sequence as set forth in SEQ ID NO: 76, and a VL comprising a sequence as set forth in SEQ ID NO: 151 ; or- comprises a VH comprising a sequence as set forth in SEQ ID NO: 310, and a VL comprising a sequence as set forth in SEQ ID NO: 311 ; and the second protein for binding to CD80 comprises the sequence of a CTLA4 protein, wherein the CTLA4 protein sequence may be derived from the soluble isoform of the protein, or transmembrane isoform (and may include an amino acid sequence as set forth in any of SEQ ID NOs: 304 to 309, 341 and 342, or CD80-binding variants thereof.

[0164] In any embodiment, the first antigen binding protein for binding to CD80 comprises a VH comprising a sequence as set forth in SEQ ID NO: 73 and a VL comprising a sequence as set forth in SEQ ID NO: 148; and the second antigen binding protein comprises a VH comprising a sequence as set forth in SEQ ID NO: 231 and a VL comprising a sequence as set forth in SEQ ID NO: 298.

[0165] In any embodiment, the first antigen binding protein for binding to CD80 comprises a VH comprising a sequence as set forth in SEQ ID NO: 74 and a VL comprising a sequence as set forth in SEQ ID NO: 149; and the second antigen binding protein comprises a VH comprising a sequence as set forth in SEQ ID NO: 231 and a VL comprising a sequence as set forth in SEQ ID NO: 298.

[0166] In one non-limiting example, the first polypeptide comprises an antigen binding domain comprising, the VL and VH regions of B5 or 19B10 in an “LH” format, wherein the VL and VH are joined via a linker region; and wherein the second polypeptide comprises an antigen binding domain comprising the VH and VL regions of B10, joined via a linker region.

[0167] In preferred embodiments of this example, the LH scFv derived from B5 or 19B10 and the HL scFv derived from B10 are each joined to an Fc region of an antibody. In particularly preferred embodiments, the Fc regions are non-identical in sequence, and preferably make use of the “knob-in-hole” technology (as defined elsewhere herein), to enable heterodimerisation of the B5 and B10 scFv-Fc fusion proteins.

[0168] Optionally, the Fc regions may comprise one or more amino acid substitutions, as defined elsewhere herein, to reduce effector function (such as the LALA-PG mutations that reduce binding to Fc receptors and which are further defined herein).

[0169] The skilled person will be familiar with alternative approaches for ensuring appropriate heterodimerisation of non-identical Fc fusion proteins, such as using the Cross-mAb or Duet-Mab technologies, also defined herein.

[0170] In further approaches, the length of the linker region between the VH and VL of each scFv may be shortened (eg to a linker length of about 8 amino acid residues compared to the typical length of about 20 amino acid residues), such that each Fv comprises a VL and VH region from different antibody chains in the assembled heterodimer. Such heterdimeric proteins may also be termed dscFvs.

[0171] In aspects of the invention directed to multiple polypeptide chains that form an antigen binding protein, an expression construct comprises a nucleic acid encoding a polypeptide comprising, e.g., a VH operably linked to a promoter and a nucleic acid encoding a polypeptide comprising, e.g., a VL operably linked to a promoter.

[0172] In another example, the expression construct is a bicistronic expression construct, e.g., comprising the following operably linked components in 5’ to 3’ order:(i) a promoter(ii) a nucleic acid encoding a first polypeptide;(iii) an internal ribosome entry site; and(iv) a nucleic acid encoding a second polypeptide, wherein the first polypeptide comprises a VH and the second polypeptide comprises a VL, or vice versa.

[0173] The present invention also contemplates separate expression constructs one of which encodes a first polypeptide comprising a VH and another of which encodes a second polypeptide comprising a VL. For example, the present invention also provides a composition comprising:(i) a first expression construct comprising a nucleic acid encoding a polypeptide comprising a VH operably linked to a promoter; and(ii) a second expression construct comprising a nucleic acid encoding a polypeptide comprising a VL operably linked to a promoter.

[0174] The invention provides a cell comprising a vector or nucleic acid described herein. Preferably, the cell is isolated, substantially purified or recombinant. In one example, the cell comprises the expression construct of the invention or:(i) a first expression construct comprising a nucleic acid encoding a polypeptide comprising a VH operably linked to a promoter; and(ii) a second expression construct comprising a nucleic acid encoding a polypeptide comprising a VL operably linked to a promoter, wherein the first and second polypeptides associate to form an antigen binding protein of the present invention.

[0175] Examples of cells of the present invention include bacterial cells, yeast cells, insect cells or mammalian cells.

[0176] The invention provides a nucleic acid encoding a bispecific molecule as herein described, an antigen binding protein, immunoglobulin variable domain, antibody, dab, scFv, Fab, Fab', F(ab')2, Fv fragment, diabody, triabody, linear antibody, single-chain antibody molecule, or multispecific antibody, fusion protein or conjugate as described herein.

[0177] The invention provides a vector comprising a nucleic acid described herein.

[0178] The invention provides a cell comprising a vector or nucleic acid described herein.

[0179] The invention provides a pharmaceutical composition comprising a bispecific molecule as described herein, a pharmaceutically acceptable carrier, diluent or excipient.

[0180] The invention provides a kit or article of manufacture comprising a bispecific molecule as described herein.

[0181] The invention provides use of a sequence according to one or more of CDR1 , CDR2, CDR3, FR1 , FR2, FR3 and FR4 as described herein to produce an antigen binding protein for binding to a CD80.

[0182] The invention provides a method for producing a bispecific molecule for binding to CD80 as described herein comprising expressing a nucleic acid as described herein in a cell or animal as described herein.

[0183] A bispecific molecule as described herein may be purified, substantially purified, isolated and / or recombinant.

[0184] A bispecific molecule of the invention may be part of a supernatant taken from media in which a hybridoma expressing an antigen binding protein of the invention has been grown.

[0185] The present invention further contemplates therapeutic and diagnostic uses for a bispecific molecule of the invention. The bispecific molecules of the invention are preferably used to treat an immune related disorder. In the most preferred embodiments of the invention, the bispecific molecules described herein are used to treat Crohn's disease, systemic lupus erythematosus (SLE), lupus nephritis, psoriatic arthritis, psoriasis, rheumatoid arthritis, ulcerative colitis, and / or transplant rejection.

[0186] Accordingly, the present invention provides a method of treating an inflammatory disorder in a subject in need thereof, the method comprising administering to said subject, a bispecific molecule or pharmaceutical composition of the invention, thereby treating an inflammatory disorder in the subject.

[0187] Further, the present invention provides for use of a bispecific molecule as described herein, in the manufacture of a medicament for the treatment of an inflammatory disorder or a condition or disorder requiring immunosuppression in a subject.

[0188] The present invention also provides a bispecific molecule or pharmaceutical composition as described herein, for use in the treatment of an inflammatory disorder or a condition or disorder requiring immunosuppression.

[0189] As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude further additives, components, integers or steps. The terms “comprising’ and “including” are used interchangeably.

[0190] Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings.

[0191] As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude further additives, components, integers or steps.

[0192] Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings.

[0193] As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude further additives, components, integers or steps.

[0194] Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings.Brief description of the drawings

[0195] Figure 1. (A) Model of the steady state T cell-APC synapse at a CD80:PD-L1 ratio of 1 :1 . (B) Model of partial PD-L1 liberation by abatacept (CTLA4-lg), allowing PD- 1 ligation while blocking CD80:CD28. (C) Model of PD-L1 liberation by prior CD80 antibody TKMF5.

[0196] Figure 2. (A) Flow cytometry of CHO cells expressing surface c / s-CD80:PD-L1 complexes incubated with abatacept or B10, measuring binding (hlgG1 staining), free PD-L1 (MIH1 staining), or CD28-lg blockade, with the model of the CD28-competing CD80 antibody below. (B) Flow cytometry of CHO cells expressing surface c / 's-CD80:PD- L1 complexes incubated with abatacept (red) or TKMF5, B5, or 19B10 (black), measuring binding (hlgG1 staining), free PD-L1 (MIH1 staining), and CD28 blockade (CD28-lg with anti-mlgG2a secondary), with the model of the PD-L1 -competing CD80 antibodies below.

[0197] Figure 3. (A) CHO cells co-transduced with approximately equivalent levels of fluorescently-linked CD80mCherry and PD-L1 mGFP, with the individual MFI values of MIH1 for the CD80mCherry+PD-L1 mGFP+ population exported. MFI data was used to generate a histogram with cells binned into equally spaced CD80mCherry:PDL1 mGFP MFI ratio intervals centred around 1 :1 . The relative fold change in MIH1 MFI of abatacept and TKMF5 to untreated cells across the CD80mCherry:PDL1 mGFP MFI ratios is plotted. (B) Models for cell-surface CD80:PD-L1 duplexes at 1 :1 (left) and 2:1 (right) ratios with PD-L1 release by abatacept (CTLA4-lg) and PD-L1 competitors TKMF5, 19B10, B5, 2B29, 2B30. Theoretical proportional release of PD-L1 by ‘partial’ (upper graph) and ‘full’ (lower graph) PD-L1 liberators across the range of CD80:PD-L1 ratios. (C) As in A for novel CD80 antibody B5 in scFv-Fc format.

[0198] Figure 4. Flow cytometry of CHO expressing cell surface c / s-CD80:PD-L1 complexes incubated with the novel CD80 antibodies in an scFv-Fc format from the unpurified supernatant of transfected 293T. Binding of the CD80 antibodies (hlgG1 staining), CD28-lg blockade (CD28mlgG2a with anti-mlgG2a secondary), and free PD- L1 (MIH1 staining) are measured against 10pg / mL purified control proteins CTLA4-lg and TKMF5.

[0199] Figure 5. Binding (hlgG1 staining) of the novel CD80 antibodies in an scFv-Fc format to CHO cells expressing human CD80, human CD80 with a mutation at the PD-L1 binding site L104D, human CD80-ALPN202 with 7 mutations in the IgV domain (H52Y, A60E, E69D, M81 L, V102M, A105G, D124G), a chimera of mouse CD80 with a human IgV domain, cynomolgus monkey CD80, and mouse CD80.

[0200] Figure 6. Flow cytometry of CHO cells expressing surface c / s-CD80:PD-L1 complexes incubated with abatacept, or the B5-B1 OscFv or 19B10-B1 OdscFv biparatopic antibodies, measuring binding (hlgG1 staining), free PD-L1 (MIH1 staining), and CD28 blockade (CD28-lg). Model of the binding of the scFv (top) and dscFv (bottom) biparatopics at the T cell-APC synapse. (B) Flow cytometry as in A showing a direct comparison of 19B10 alone or in the 19B10-B1 OdscFv biparatopic format with abatacept control.

[0201] Figure 7. Model of the binding of full-length biparatopics at the T cell-APC synapse. Flow cytometry of CHO cells expressing surface c / s-CD80:PD-L1 complexes incubated with abatacept or the 19B10-B1 OdscFv (top) or full-length 19B10-B10 (bottom) biparatopic antibodies, measuring binding (hlgG1 staining), free PD-L1 (MIH1 staining), and high-affinity CTLA4-lg blockade (MEDI5265 with anti-mlgG2a secondary).

[0202] Figure 8. Abatacept and 19B10-B1 OdscFv dose / response on c / s-CD80:PD-L1 CHO cells measuring PD-L1 liberation (free PD-L1 by MIH1 antibody staining) and blockade of high-affinity CTLA4-lg (MFI of MEDI5265 with anti-mlgG2a secondary).

[0203] Figure 9. (A) MFI of free PD-L1 and relative CD28-lg blockade to abatacept on c / s-CD80:PD-L1 expressing CHO cells for parental antibodies TKMF5, B5, 19B10, and B10 to B5-B1 OscFv and 19B10-B1 OdscFv biparatopic antibodies. (B) Relative free PD- L1 to untreated for 19B10 and 19B10-B1 OdscFv treated c / s-CD80mCherry:PD-L1 mGFP cells across the cell surface ratios.

[0204] Figure 10. Flow cytometry of c / s-CD80:PD-L1 cells incubated with abatacept or B5-B1 OscFv measuring binding (hlgG1 staining), free PD-L1 (MIH1 staining), and high- affinity CTLA4-lg blockade (MEDI5265 with anti-mlgG2a secondary). Direct comparison of relative PD-L1 liberation across a dose / response and the CD80:PD-L1 ratios on cis- CD80mCherry:PD-L1 mGFP cells for the B5-B1 OscFv and 19B10-B1 OdscFv biparatopics.

[0205] Figure 11. Naive primary T cell activation assay from a healthy donor measuring T cell proliferation (CFSE dilution) and induction of CD69, directly assessing costimulation blockade by parental and biparatopic antibodies.

[0206] Figure 12. (A) Percentage of human residues within the Fv regions of the indicated biologies. (B) CD28 blockage and PD-L1 liberation activity is not compromised by CD80 antibody humanisation.

[0207] Figure 13. (A-B) Model of the binding of the anti-mouse CD80 biparatopic TKMG48-1610A1 scFv at the T cell-APC synapse, and theoretical liberation of CD80:PD- L1 duplexes at ratios of 1 :1 and 2:1. (C) Flow cytometry of c / s-mCD80eBFP:mPD- Ll mCherry cells incubated with abatacept, parental antibodies 1610A1 or TKMG48, or TKMG48-161 OAlscFv biparatopic measuring binding (hlgG1 staining), free PD-L1 (MIH1 staining), and high-affinity CTLA4-lg blockade (MEDI5265 with anti-mlgG2a secondary).(D) PD-L1 liberation across the mCD80eBFP:mPD-L1 mCherry ratios from cells in C.

[0208] Figure 14. (A-B) The bifunctional B5scFv-sCTLA4 biologic effectively blocks CD80:CD28 interactions and liberates PD-L1. (C) B5scFv-sCTLA4 liberates PD-L1 across a broad range of CD80:PD-L1 ratios. (D) B5scFv-sCTLA4 is also predicted to block CD80:CD28 interactions in scenarios where APCs express both CD80 and CD86.(E) Flow cytometry of c / s-CD80:PD-L1 cells incubated with abatacept, or 19B10scFv- sCTLA4 or B5-sCTLA4 bifunctionals that incorporate either wild type sCTLA4, sBelatacept, or SMEDI5265, measuring binding (hlgG1 staining), free PD-L1 (MIH1 staining), and high-affinity CTLA4-lg blockade (MEDI5265 with anti-mlgG2a secondary).

[0209] Figure 15. (A-B) The bifunctional TKMG48scFv-sCTLA4 biologic effectively blocks mCD80:CD28 interactions and liberates PD-L1. (C) TKMG48scFv-sCTLA4 liberates mPD-L1 across a broad range of mCD80:mPD-L1 ratios.

[0210] Figure 16. (A) Schematics of multiple biparatopic anti-CD80 formats including heterodimeric knob-in-hole (PP, FP, PF, FF) and single chain (FFT). (B) Changes in free PD-L1 (MIH1 ) and CTLA4HA-lg (high affinity CD28 surrogate) blockade by several B5B10 biparatopic antibodies on cis-CD80:PD-L1 cells relative to untreated. (C) Average free PD-L1 (MIH1 MFI) across CD80mCherry:PD-L1 mGFP ratio intervals when untreated or treated with abatacept or alternate B5B10 biparatopic formats. (D) Cartoon schematic of a tetravalent homodimeric tandem scFv B5B10 biparatopic format, and flow cytometry demonstrating superior PD-L1 liberation relative to abatacept.

[0211] Figure 17. Fold change in free PD-L1 (MIH1 staining, top) and relative blockade of CTLA4HA-lg binding (bottom) on cis-CD80:PD-L1 cells by biparatopic heterodimericscFv-Fc antibodies with different antibody clones or CTLA4s. B10, 2B2, 2B17, 2B26, and CTLA4s, or 19B10, B5, 2B29, and 2B30 represent the costimulation blocking hole or PD- L1 liberating knob arms of the biparatopic respectively.

[0212] Figure 18. (A) Schematic of the humanisation strategy for mouse CD80 and PD-L1 genes. Homologous human sequences replace exon 2 of mouse CD80, which encodes the IgV domain bound by the human CD80 antibodies, and exon 3 of mouse PD-L1 . Double knockin (DKI) mice maintain endogenous regulation and expression CD80 and PD-L1 , and retain binding in cis to each other as well as in trans to CD28, CTLA4, or PD-1. (B) Schematic of the anti-GBM glomerulonephritis mouse model of kidney autoimmunity. (C) Kidney damage measured by the urine albumin:creatinine ratio (uACR) showing improved protection by biparatopic B5B10 relative to abatacept.

[0213] Figure 19. (A) In vitro primary human T cell activation as assessed by the percentage of IL-2+ T cells following 4 day co-culture with artificial antigen presenting cells (aAPCs) expressing a 1 :1 ratio of CD80:PD-L1 and cell surface OKT3scFv. 50 pg / mL of abatacept or B5-B10 biparatopic were added in the final 8 hours of co-culture. (B) A dose / response of the experimental conditions described in A, showing reduced CD4 and CD8 T cell activity by B5-B10 relative to abatacept. (C) Activity in CD4 T cells treated as described in A, demonstrating relative contribution of PD-1 signalling by abatacept and B5-B10 by addition of an anti-PD-1 antibody (nivolumab).Sequence information

[0214] Tables comprising sequence information:Table 1 : VH CDR sequences - antigen binding proteins inhibiting binding of PD-L1 toCD80Table 2: VH framework (FR) sequences - antigen binding proteins inhibiting binding ofPD-L1 to CD80Table 3: VH full sequences - antigen binding proteins inhibiting binding of PD-L1 toCD80Table 4: VL CDR sequences - antigen binding proteins inhibiting binding of PD-L1 toCD80Table 5: VL framework sequences - antigen binding proteins inhibiting binding of PD-L1 to CD80Table 6: VL full sequences - antigen binding proteins inhibiting binding of PD-L1 toCD80Table 7: VH CDR sequences - antigen binding proteins inhibiting binding of CD28 toCD80Table 8: VH framework (FR) sequences - antigen binding proteins inhibiting binding ofCD28 to CD80Table 9: VH full sequences - antigen binding proteins inhibiting binding of CD28 to CD80Table 10: VL CDR sequences - antigen binding proteins inhibiting binding of CD28 toCD80Table 11 : VL framework sequences - antigen binding proteins inhibiting binding of CD28 to CD80Table 12: VL full sequences - antigen binding proteins inhibiting binding of CD28 toCD80Table 13: CTLA4-derived sequencesTable 14: Sequence of prior antigen binding proteins for inhibiting binding of PD-L1 toCD80Detailed description of the embodiments

[0215] It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.

[0216] Reference will now be made in detail to certain embodiments of the invention. While the invention will be described in conjunction with the embodiments, it will be understood that the intention is not to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims.

[0217] One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.

[0218] All of the patents and publications referred to herein are incorporated by reference in their entirety.

[0219] For purposes of interpreting this specification, terms used in the singular will also include the plural and vice versa.

[0220] The general chemical terms used in the formulae herein have their usual meaning.The CTLA4 / CD80 / CD86 axis

[0221] The CTLA4 immune checkpoint restrains T cell activity and prevents autoimmunity. T cell surface CTLA4 inhibits CD28 receptor costimulatory signaling by sequestering their shared ligands CD80 and CD86 (B7-1 and B7-2, respectively) expressed on antigen-presenting cells (APCs). Similarly, recombinant CTLA4-lg fusion proteins including abatacept block costimulation and are effective therapies in autoimmune disease and organ transplantation.

[0222] Recent studies show that CD80 and the co-inhibitory ligand PDL1 interact in cis on the same APC surface, but how this affects CTLA4 and PD1 checkpoint function is poorly understood.

[0223] The present invention is based on the surprising finding by the inventors that it is possible to simultaneously block PD-L1 and CD28 binding to CD80, and to thereby provide superior immunosuppression compared to currently existing immunosuppressants for use in the clinic.

[0224] In particular, the inventors have demonstrated that by simultaneously blocking the binding of PD-L1 and CD28 to CD80, using the bispecific molecules of the present invention, greater immunosuppression is likely to be provided compared to abatacept.Indeed the inventors have shown that while abatacept can prevent binding of CD28 to CD80, it only partially liberates the binding of PD-L1 from CD80.

[0225] It will be appreciated that the bispecific molecules of the invention comprise a first portion in the form of a first polypeptide for binding to CD80 and inhibiting the binding thereto by PD-L1 ; and a second portion in the form of a second polypeptide for binding to CD80 and inhibiting the binding thereto by CD28.First polypeptide: inhibition of PD-L1 binding to CD80

[0226] In any embodiment herein, the first polypeptide comprises an antigen binding protein. Non-limiting examples of antigen binding proteins for binding to CD80 and which block the binding of PD-L1 to CD80 are defined in the tables herein, and are named B5, 19B10, 2B29 and 2B30. However, it will be appreciated that any antibody or antigen binding fragment thereof, capable of binding to CD80 and preventing / reducing / blocking the binding of PD-L1 , could be used. Other known antibodies in this category include the antibody TKMF5 (as disclosed in W02020116636, incorporated herein by reference).

[0227] It will be appreciated that in preferred embodiments, upon binding of the first polypeptide to CD80, PD-L1 is prevented (or partially prevented) from binding to CD80 (or partially or completely liberated from binding to CD80) such that substantially all PD- L1 molecules are not cis bound to CD80 (and are therefore free to bind to PD-1 ). This is to be contrasted with the binding of an anti-CD80 antibody of the prior which does not liberate PD-L1 such that upon binding, PD-L1 remains substantially c / s-bound to CD80. A schematic representation of graded (partial) liberation of PD-L1 compared to nonliberation of PDL1 is provided herein in Figure 1 B. As shown in the figure, binding of Abatacept (a prior art CD80-binder comprised of CTLA4-Fc), provides only partial liberation of PD-L1 from CD80, whereas the antigen binding proteins B5, 19B10 (also 2B29, 2B30 and TKMF5), facilitate full liberation of PD-L1 (as compared to abatacept). Moreover, the inventors believe that the degree of liberation of PD-L1 provided by abatacept is generally dependent on the ratio of the number of PD-L1 and CD80 molecules on the cell surface. Conversely, liberation of PD-L1 binding by the antigen binding proteins described herein, it typically independent of this ratio.

[0228] As used herein the terms “liberation” and “release” with respect to the interaction of CD80 and PD-L1 , may be used interchangeably. The terms will be understood to referto the reduction of molecular interactions between CD80 and PD-L1 such that upon “liberation” or “release”, PD-L1 is no longer bound to CD80 on the surface of a cell (and thereby making PD-L1 available to bind to PD-1 ).

[0229] As used herein, “remains substantially c / s-bound to CD80” refers to a situation for which there is minimal liberation (release) of PD-L1 from binding to CD80. For example, “remains substantially c / s-bound to CD80” suggests that no more than 10%, no more than 9%, no more than 8%, no more than 7%, no more than 6%, no more than 5%, no more than 4%, no more than 3% or no more than 2% of PD-L1 is liberated (ie released) from c / s-binding to CD80 upon binding of an antigen binding protein herein. Typically the degree of binding may be made in comparison to abatacept.

[0230] Where PD-L1 is partially liberated from c / s-binding to CD80, the percentage of PD-L1 molecules liberated is no more than 15%, no more than 20%, no more than 25%, no more than 30%, no more than 40%, no more than 50%, no more than 60%, no more than 70% or no more than 80%, preferably no more than 50%. Typically the degree of binding may be made in comparison to abatacept.

[0231] As used herein, “substantially liberated from CD80” refers to a situation for which there is complete or near complete liberation of PD-L1 from binding to CD80. Preferably, “substantially liberated from CD80” suggests that no more than 10%, no more than 9%, no more than 8%, no more than 7%, no more than 6%, no more than 5%, no more than 4%, no more than 3% or no more than 2% of PD-L1 remains c / s-bound to CD80 upon binding of an antigen binding protein of the invention to CD80. Preferably, “substantially liberated from CD80” suggests that less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3% or less than 2% of PD-L1 remains c / s-bound to CD80 upon binding of an antigen binding protein of the invention to CD80. In other words, “substantially liberated from CD80” suggests that at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98% or at least about 99% or all of PD-L1 is liberated from CD80 upon binding of an antigen binding protein as described herein, to CD80. Typically the degree of binding may be made in comparison to abatacept.

[0232] The skilled person will be familiar with methods for determining the binding of any antigen binding protein of the invention to CD80, including according to any of the methods described herein in the Examples.

[0233] Moreover, the skilled person will be able to determine the binding of an antigen binding protein to CD80, including whether a protein of the invention thereby facilitates liberation of PD-L1 from its binding to CD80. In other words, it will be within the purview of the skilled person to determine whether, upon binding of a protein of the invention to CD80, PD-L1 remains bound to CD80, including in comparison to other known CD80 binding proteins. Such methods are also described herein, in the Examples.

[0234] Further examples of methods for determining binding of a protein to CD80 and / or extent of liberation of PD-L1 upon binding of a protein to CD80 are described in Sugiura et al., (Nature Immunol. 2022, 23: 399-410) Tekguc et al., (PNAS, 2021 ; 119(30) e2023739117) and Oxley et al., (2024) Cell Reports 43:114834, each of which is incorporated herein by reference.Second polypeptide: inhibition of CD28 binding to CD80

[0235] In certain embodiments, the second polypeptide comprises a native binding partner of CD80, or a functional homologue or derivative thereof, and that preferably binds to the same or similar site on CD80 as CD28 and which therefore prevents binding of CD28 to CD80.

[0236] In one example, the second polypeptide comprises the amino acid sequence of a CTLA4 polypeptide, or a fragment, derivative or portion of the CTLA4 protein. In certain embodiments, the CTLA4 polypeptide may comprise a CTLA4 mutant molecule (such as variant of CTLA4 with altered affinity for CD80).

[0237] As used herein, a CTLA4 polypeptide or a CTLA4 domain comprises a CD80 / CD86-binding domain of CTLA4. Typically, the sequence is derived from an endogenous (eg wild-type) CTLA4 molecule, although in certain embodiments, the sequence may be from a mutant CTLA4 molecule or a fragment thereof or a portion thereof. The mutant CTLA4 molecule may have increased binding affinity for CD80.

[0238] Preferably the CTLA4 polypeptide has the amino acid sequence of the naturally occurring, full length transmembrane isoform of CTLA4 (U.S. Pat. Nos. 5,434,131 ,5,844,095, 5,851 ,795), or the extracellular domain thereof, which binds CD80 and / or CD86, and / or interferes with CD80 and / or CD86 from binding their receptors.

[0239] Exemplary amino acid sequences of “wild-type” CTLA4 sequence are provided in Table 12 as SEQ ID NOs: 304 to 309, 341 and 342, with the ligand binding sequence shown in SEQ ID NO: 304. (The N-terminal signal peptide is not shown in this sequence). It will be appreciated that wild-type CTLA4 sequences may comprise alternative N- terminal leader sequences which may alter the N-terminal sequence relative to SEQ ID NO:s 304 to 309, 341 and 342. Such variants are included within the scope of the present invention. In one example, the sequence of the wild type CTLA4 sequence may be as described in the NCBI database at accession number NP 005205.2.

[0240] Endogenous CTLA4 may exist as a cell surface protein, having an N-terminal extracellular domain, a transmembrane domain, and a C-terminal cytoplasmic domain. The extracellular domain binds to target antigens, such as CD80 and CD86. In a cell, the naturally occurring, CTLA4 protein is translated as an immature polypeptide, which includes a signal peptide at the N-terminal end. The immature polypeptide undergoes post-translational processing, which includes cleavage and removal of the signal peptide to generate a CTLA4 cleavage product having a newly generated N-terminal end that differs from the N-terminal end in the immature form. One skilled in the art will appreciate that additional post-translational processing may occur, which removes one or more of the amino acids from the newly generated N-terminal end of the CTLA4 cleavage product. The mature form of the CTLA4 molecule includes the extracellular domain of CTLA4, or any portion thereof, which binds to CD80 and / or CD86.

[0241] As used herein “the extracellular domain of CTLA4” is a portion of the CTLA4 that recognizes and binds CD80 and / or CD86. For example, an extracellular domain of CTLA4 comprises methionine at position 1 to aspartic acid at position +124. Alternatively, an extracellular domain of CTLA4 comprises alanine at position -1 to aspartic acid at position +124. The extracellular domain includes fragments or derivatives of CTLA4 that bind CD80 and / or CD86.

[0242] As used herein “a CTLA4 mutant molecule” comprises any variant of a CTLA4 molecule (such as any variant of the amino acid sequence set forth in SEQ ID NO: 304 to 309, 341 or 342), wherein the molecule recognizes and binds its target, e.g., CD80 and / or CD86.

[0243] In any embodiment, a CTLA 4 variant or mutant molecule comprises any variant of a CTLA4 molecule (such as any variant of the amino acid sequence set forth in SEQ ID NO: 304 to 309, 341 or 342, wherein the molecule recognizes and binds to CD80 but does not bind to CD86 (eg the Y1 OOF CTLA4 variant as further described herein).

[0244] As used herein a “fragment of a CTLA4 mutant molecule” is a part of a CTLA4 mutant molecule, preferably the extracellular domain of CTLA4 or a part thereof, that recognizes and binds its target, e.g., CD80 and / or CD86.

[0245] As used herein a “derivative of a CTLA4 mutant molecule” is a molecule that shares at least 70% sequence similarity with and functions like the extracellular domain of CTLA4, i.e., it recognizes and binds CD80 and / or CD86.

[0246] As used herein, a “portion of a CTLA4 molecule” includes fragments and derivatives of a CTLA4 molecule that binds CD80 and / or CD86.

[0247] As used herein “a position equivalent thereto” refers to an amino acid residue that is at an equivalent position within the CTLA4 protein but may be defined according to a different numbering convention. The skilled person will be able to determine which amino acid position is being referred to by the context of the surrounding amino acid sequences. For example, the arginine residue in the context of the amino acid sequence ATEVRVTVL is numbered residue R34 according to the numbering of SEQ ID NO: 304, but may be referred to differently according to a different numbering convention.

[0248] Included within the scope of the present invention, are proteins wherein the second polypeptide comprises additional variations to the CTLA4 sequence, for example, to improve binding affinity for the ligands of CTLA4. In certain examples, the first portion further includes one or more of the substitutions selected from the group consisting of A30E, A30F, A30H, A30K, A30N, A30Q, A30R, T31 E, T31 H, T31 R, T31 V, E32D, E32I, E32M, E32T, E32V, R34E, R34F, R341 , R34L, R34M, R34Q, R34T, R34W, R34Y, T36D, T36E, T36F, T36M, T36V, T356, A50D, A50E, A50F, A50T, A50W, A50Y, T52D, T52E, T52H, T52L, T52N, T52Q, T52R, T52S, T52V, M54E, M54F, M54H, M54Q, M54W, M54Y, T60H, T601 , T60L, T60N, T60Q, T60V, T60Y, L62A, L62D, L62E, L62F, L62G, L62H, L62I, L62K, L62M, L62N, L62P, L62Q, L62R, L62S, L62T, L62V, L62W, L62Y, D64E, S65K, S65R, S65Y, K94D, K94E, K94F, K94H, K94N, K94Q, K94R, K94S, K94T, K94V, K94W, K94Y, E96D, E96H, E96L, E96Q, E96Y, M98D, M98F, M98I, M98N, M98V,Y99F, Y99W, Y103F, Y103W, Y104D, Y104E, Y104F, Y104H, Y104N, Y104Q, Y104W, L105F, L105H, L105M, L105V, L105Y, G106D, G106E, I107E, and I107Y (numbering according to SEQ ID NO: 304. It will be well within the purview of the skilled person to determine the particular amino acid substitutions listed above, if comparing to an alternative numbering convention for CTLA4. For example, the “Y100F” substitution sometimes referred to in the literature is numbered Y99F according to the numbering of any of SEQ ID NO: 304. Other variants contemplated by the present invention include 117R, A25T, S26N, G28S, L59A, S71 A and M86Q (numbered according to any of SEQ ID NOs: 304).

[0249] In further embodiments, the second polypeptide may comprise an amino acid sequence derived from the soluble isoform (non-membrane bound form) of CTLA4, or a functional variant thereof. An exemplary amino acid sequence of mature, soluble CTLA4 is provided in Table 13 as SEQ ID NO: 306.

[0250] In alternative embodiments, the second polypeptide may comprise an antigen binding protein. Non-limiting examples of antigen binding proteins for binding to CD80 and which inhibit the binding of CD28 to CD80 are defined in the tables herein, and are named B10, B7, 2B2, 2B17 and 2B26.Antigen binding proteins

[0251] As used herein, the terms “antigen binding protein” and “antibody” may be used interchangeably.

[0252] The description and definitions of variable regions and parts thereof, immunoglobulins, antibodies and fragments thereof herein may be further clarified by thedefinitions provided further herein.

[0253] As used herein, the term “antigen binding domain” and shall be taken to mean a region of an antibody that is capable of specifically binding to an antigen, i.e. , a VH or a VL or an Fv comprising both a VH and a VL. The antigen binding domain need not be in the context of an entire antibody, e.g., it can be in isolation (e.g., a domain antibody) or in another form, e.g., as described herein, such as a dscFv.

[0254] For the purposes for the present disclosure, the term “antibody” includes a protein capable of specifically binding to one or a few closely related antigens by virtue ofan antigen binding domain contained within a Fv. This term includes four chain antibodies (e.g., two light chains and two heavy chains), recombinant or modified antibodies (e.g., chimeric antibodies, humanised antibodies, human antibodies, CDR-grafted antibodies, primatised antibodies, de-immunised antibodies, synhumanised antibodies, halfantibodies, bispecific antibodies).

[0255] An antibody generally comprises constant domains, which can be arranged into a constant region or constant fragment or fragment crystallisable (Fc). Exemplary forms of antibodies comprise a four-chain structure as their basic unit. Full-length antibodies comprise two heavy chains (~50 to 70 kD) covalently linked and two light chains (~23 kDa each). A light chain generally comprises a variable region (if present) and a constant domain and in mammals is either a K light chain or a A light chain. A heavy chain generally comprises a variable region and one or two constant domain(s) linked by a hinge region to additional constant domain(s). Heavy chains of mammals are of one of the following types a, 5, £, y, or p. Each light chain is also covalently linked to one of the heavy chains. For example, the two heavy chains and the heavy and light chains are held together by inter-chain disulfide bonds and by non-covalent interactions. The number of inter-chain disulfide bonds can vary among different types of antibodies. Each chain has an N- terminal variable region (VH or VL wherein each are ~ 110 amino acids in length) and one or more constant domains at the C- terminus. The constant domain of the light chain (CL which is -110 amino acids in length) is aligned with and disulfide bonded to the first constant domain of the heavy chain (Cm which is 330 to 440 amino acids in length). The light chain variable region is aligned with the variable region of the heavy chain. The antibody heavy chain can comprise 2 or more additional CH domains (such as, CH2, CHS and the like) and can comprise a hinge region between the Cm and CH2 constant domains. Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG 1 , lgG2, IgGs, lgG4, IgAi and lgA2) or subclass. In one example, the antibody is a murine (mouse or rat) antibody or a primate (such as, human) antibody. In one example the antibody heavy chain is missing a C-terminal lysine residue. In one example, the antibody is humanised, synhumanised, chimeric, CDR-grafted or deimmunised.

[0256] The terms "full-length antibody", "intact antibody" or "whole antibody" are used interchangeably to refer to an antibody in its substantially intact form, as opposed to an antigen binding fragment of an antibody. Specifically, whole antibodies include those with heavy and light chains including an Fc region. The constant domains may be wild-typesequence constant domains (e.g., human wild-type sequence constant domains) or amino acid sequence variants thereof.

[0257] As used herein, “variable region” refers to the portions of the light and / or heavy chains of an antibody as defined herein that is capable of specifically binding to an antigen and, includes amino acid sequences of complementarity determining regions (CDRs); i.e., CDRi, CDR2, and CDR3, and framework regions (FRs). For example, the variable region comprises three or four FRs (e.g., FR1, FR2, FR3 and optionally FR4) together with three CDRs. VH refers to the variable region of the heavy chain. VL refers to the variable region of the light chain.

[0258] As used herein, the term “complementarity determining regions” (syn. CDRs; i.e., CDR1 , CDR2, and CDR3) refers to the amino acid residues of an antibody variable region the presence of which are major contributors to specific antigen binding. Each variable region domain (VH or VL) typically has three CDRs identified as CDR1 , CDR2 and CDR3. The CDRs of VH are also referred to herein as CDR H1 , CDR H2 and CDR H3, respectively, wherein CDR H1 corresponds to CDR 1 of VH, CDR H2 corresponds to CDR 2 of VH and CDR H3 corresponds to CDR 3 of VH. (Alternatively, the CDRs may be named HCDR1 , HCDR2 and HCDR3). Likewise, the CDRs of VL are referred to herein as CDR L1 , CDR L2 and CDR L3, respectively, wherein CDR L1 corresponds to CDR 1 of VL, CDR L2 corresponds to CDR 2 of VL and CDR L3 corresponds to CDR 3 of VL. (Alternatively, the CDRs in the light variable region may be named LCDR1 , LCDR2 and LCDR3)

[0259] "Framework" or "FR" residues are those variable domain residues other than the hypervariable region or CDR residues herein defined. The FRs of VH are also referred to herein as FR H1 , FR H2, FR H3 and FR H4, respectively, wherein FR H1 corresponds to FR 1 of VH, FR H2 corresponds to FR 2 of VH, FR H3 corresponds to FR 3 of VH and FR H4 corresponds to FR 4 of VH. Likewise, the FRs of VL are referred to herein as FR L1 , FR L2, FR L3 and FR L4, respectively, wherein FR L1 corresponds to FR 1 of VL, FR L2 corresponds to FR 2 of VL, FR L3 corresponds to FR 3 of VL and FR L4 corresponds to FR 4 of VL.

[0260] In any embodiment, the amino acid positions assigned to CDRs and FRs may be defined according to Kabat Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., 1987 and 1991 (also referred to herein as “theKabat numbering system”). It will be appreciated that in accordance with the present invention, the system used to define FRs and CDRs is not limited to the Kabat numbering system, but includes all numbering systems, including the canonical numbering system of Chothia and Lesk J. Mol. Biol. 196: 901 -917, 1987; Chothia et al., Nature 342: 877-883, 1989; and / or Al-Lazikani et aL, J. Mol. Biol. 273: 927-948, 1997; the numbering system of Honnegher and Plukthun J. Mol. Biol. 309: 657-670, 2001 ; or the IMGT system discussed in Giudicelli et aL, Nucleic Acids Res. 25: 206-211 1997. In another example, the amino acid positions assigned to CDRs and FRs may be defined according to the Martin (Enhanced Chothia) Numbering Scheme (http: / / www.bioinfo.org.uk / abs / info.html). In some examples, the CDRs may be defined according to the AbM numbering system. The AbM system represents a compromise between the Kabat and Chothia structural loops, and is used by Oxford Molecular's AbM antibody-modeling software. In some examples, the CDRs may be “contact” CDRs. The “contact” CDRs are based on an analysis of the available complex crystal structures.

[0261] In one example, the CDRs are defined according to the Kabat numbering system. Optionally, heavy chain CDR2 according to the Kabat numbering system does not comprise the five C-terminal amino acids listed herein or any one or more of those amino acids are substituted with another naturally-occurring amino acid. In this regard, Padlan et aL, FASEB J., 9: 133-139, 1995 established that the five C-terminal amino acids of heavy chain CDR2 are not generally involved in antigen binding.

[0262] The different systems used for assigning CDRs and FRs of an antigen binding domain are well known to the skilled person and are summarised in the below table:

[0263] 1Some of these definitions (particularly for Chothia loops) vary depending on the individual publication examined.

[0264] 2The end of the Chothia CDR H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop. This is because the Kabat numbering scheme places the insertions at H35A and H35B: if neither H35A nor H35B is present, the loop ends at H32; if only H35A is present, the loop ends at H33; if both H35A and H35B are present, the loop ends at H34.

[0265] As used herein, the term “Fv” shall be taken to mean any protein, whether comprised of multiple polypeptides or a single polypeptide, in which a VL and a VH associate and form a complex having an antigen binding domain, i.e., capable of specifically binding to an antigen. The VH and the VL that form the antigen binding domain can be in a single polypeptide chain or in different polypeptide chains. Furthermore, an Fv of the invention (as well as any protein of the invention) may have multiple antigen binding domains that may or may not bind the same antigen. This term shall be understood to encompass fragments directly derived from an antibody as well as proteins corresponding to such a fragment produced using recombinant means. In some examples, the VH is not linked to a heavy chain constant domain (CH) 1 and / or the VL is not linked to a light chain constant domain (CL). Exemplary Fv containing polypeptides or proteins include a Fab fragment, a Fab’ fragment, a F(ab’) fragment, a scFv, a diabody, a triabody, a tetrabody or higher order complex, or any of the foregoing linked to a constant region or domain thereof, e.g., CH2 or CH3 domain, e.g., a minibody.

[0266] Diabodies are constructed by connecting heavy chain variable fragments (VH) and light-chain variable fragments (VL) with a flexible linker, preferably of between about 5~8 but up to 15 or under 20 amino acids. In the single chain Fv, the linker connecting two fragments is usually longer (about 20 amino acids). These longer linkers allow intramolecular interaction between the VH and VL domains in the single polypeptide chain. In diabodies, the VH and VL domains in the same polypeptide chain cannot associate because the linker is too short. Instead, the VH and VL domains from different chains form a dimer having two functional Fv domains. Diabodies containing two identical Fv domains are called monospecific diabodies.

[0267] A "Fab fragment" consists of a monovalent antigen-binding fragment of an immunoglobulin and can be produced by digestion of a whole antibody with the enzyme papain, to yield a fragment consisting of an intact light chain and a portion of a heavy chain or can be produced using recombinant means. A "Fab' fragment" of an antibody 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. A Fab’ fragment can also be produced by recombinant means. A "F(ab')2 fragment” of an antibody consists of a dimer of two Fab' fragments held together by two disulfide bonds, and is obtained by treating a whole antibody molecule with the enzyme pepsin, without subsequent reduction. A “Fab2” fragment is a recombinant fragment comprising two Fab fragments linked using, for example a leucine zipper or a CH3 domain. A “single chain Fv” or “scFv” is a recombinant molecule containing the variable region fragment (Fv) of an antibody in which the variable region of the light chain and the variable region of the heavy chain are covalently linked by a suitable, flexible polypeptide linker.

[0268] As used herein, the term “binds” in reference to the interaction of an antigen binding protein or an antigen binding domain thereof with an antigen means that the interaction is dependent upon the presence of a particular structure (e.g., an antigenic determinant or epitope) on the antigen. For example, an antibody recognizes and binds to a specific protein structure rather than to proteins generally. If an antibody binds to epitope "A", the presence of a molecule containing epitope “A” (or free, unlabelled “A”), in a reaction containing labelled “A” and the protein, will reduce the amount of labelled “A” bound to the antibody.

[0269] As used herein, the term “specifically binds” or “binds specifically” shall be taken to mean that an antigen binding protein of the invention reacts or associates more frequently, more rapidly, with greater duration and / or with greater affinity with a particular antigen or cell expressing same than it does with alternative antigens or cells. For example, an antigen binding protein binds to CD80 with materially greater affinity (e.g., 1 .5 fold or 2 fold or 5 fold or 10 fold or 20 fold or 40 fold or 60 fold or 80 fold to 100 fold or 150 fold or 200 fold) than it does to other related molecules. Generally, but not necessarily, reference to binding means specific binding, and each term shall be understood to provide explicit support for the other term.

[0270] As used herein, the term “does not detectably bind” shall be understood to mean that an antigen binding protein, e.g. an antibody, binds to a candidate antigen at a level less than 10%, or 8% or 6% or 5% above background. The background can be the level of binding signal detected in the absence of the protein and / or in the presence of a negative control protein (e.g., an isotype control antibody) and / or the level of binding detected in the presence of a negative control antigen. The level of binding is detected using biosensor analysis (e.g. Biacore) in which the antigen binding protein is immobilised and contacted with an antigen.

[0271] As used herein, the term “does not significantly bind” shall be understood to mean that the level of binding of an antigen binding protein of the invention to a polypeptide is not statistically significantly higher than background, e.g., the level of binding signal detected in the absence of the antigen binding protein and / or in the presence of a negative control protein (e.g., an isotype control antibody) and / or the level of binding detected in the presence of a negative control polypeptide. The level of binding is detected using biosensor analysis (e.g. Biacore or Blitz) in which the antigen binding protein is immobilised and contacted with an antigen.

[0272] As used herein, the term “epitope” (syn. “antigenic determinant”) shall be understood to mean a region of CD80 to which an antigen binding protein comprising an antigen binding domain of an antibody binds. Unless otherwise defined, this term is not necessarily limited to the specific residues or structure to which the antigen binding protein makes contact. For example, this term includes the region spanning amino acids contacted by the antigen binding protein and 5-10 (or more) or 2-5 or 1 -3 amino acids outside of this region. In some examples, the epitope comprises a series of discontinuous amino acids that are positioned close to one another when antigen binding protein is folded, i.e. , a “conformational epitope”. The skilled artisan will also be aware that the term "epitope" is not limited to peptides or polypeptides. For example, the term “epitope” includes chemically active surface groupings of molecules such as sugar side chains, phosphoryl side chains, or sulfonyl side chains, and, in certain examples, may have specific three-dimensional structural characteristics, and / or specific charge characteristics.

[0273] Methods for generating antibodies are known in the art and / or described in Harlow and Lane (editors) Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, (1988). Generally, in such methods CD80 or a region thereof (e.g., anextracellular region) or immunogenic fragment or epitope thereof or a cell expressing and displaying same (i.e. , an immunogen), optionally formulated with any suitable or desired carrier, adjuvant, or pharmaceutically acceptable excipient, is administered to a nonhuman animal, for example, a mouse, chicken, rat, rabbit, guinea pig, dog, horse, cow, goat or pig. The immunogen may be administered intranasally, intramuscularly, subcutaneously, intravenously, intradermally, intraperitoneally, or by other known route.

[0274] The antibody may be a synthetic antibody. For example, the antibody is a chimeric antibody, a humanised antibody, a human antibody synhumanised antibody, primatised antibody or a de-immunised antibody.Preferably the antibody is a recombinant antibody. The term “recombinant” shall be understood to mean the product of artificial genetic recombination. Accordingly, in the context of a recombinant protein comprising an antibody antigen binding domain, this term does not encompass an antibody naturally-occurring within a subject’s body that is the product of natural recombination that occurs during B cell maturation. However, if such an antibody is isolated, it is to be considered an isolated protein comprising an antibody antigen binding domain. Similarly, if nucleic acid encoding the protein is isolated and expressed using recombinant means, the resulting protein is a recombinant protein comprising an antibody antigen binding domain. A recombinant protein also encompasses a protein expressed by artificial recombinant means when it is within a cell, tissue or subject, e.g., in which it is expressed.Fc regions

[0275] In any aspect or embodiment of the invention, the first and / or second polypeptides of the bispecific molecule may comprise an Fc region of an antibody.

[0276] The Fc portion of the proteins of the invention are comprised of the Fc region or some portion of the Fc region of an antibody. Antibodies are immunoglobulins that bind a specific antigen. In most mammals, including humans and mice, antibodies are constructed from paired heavy and light polypeptide chains. The light and heavy chain variable regions show significant sequence diversity between antibodies, and are responsible for binding the target antigen. Each chain is made up of individual immunoglobulin (Ig) domains, and thus the generic term immunoglobulin is used for such proteins.

[0277] The term “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. In other words, the Fc region contains two heavy chain fragments comprising the CH2 and CH3 domains of an antibody. In the context of the present invention, the Fc region comprises two heavy chain fragments, preferably the CH2 and CH3 domains of said heavy chain. The two heavy chain fragments are held together by two or more disulfide bonds and by hydrophobic interactions of the CH3 domains.

[0278] In some aspects, the fusion protein does not exhibit any effector function or any detectable effector function. “Effector functions” or “effector activities” refer to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: C1q binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody dependent cell- mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g. B cell receptor); and B cell activation. In vitro and / or in vivo cytotoxicity assays can be conducted to confirm the reduction / depletion of CDC and / or ADCC activities. For example, Fc receptor (FcR) binding assays can be conducted to ensure that the antibody lacks FcyR binding (hence likely lacking ADCC activity), but retains FcRn binding ability. The primary cells for mediating ADCC, NK cells, express FcyRIII only, whereas monocytes express FcyRI, FcyRII and FcyRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457- 492 (1991 ). Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest is described in U.S. Patent No. 5,500,362 (see, e.g., Hellstrom, I. et al. Proc. Nat’l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I et al., Proc. Nat’l Acad. Sci. USA 82:1499-1502 (1985); 5,821 ,337 (see Bruggemann, M. et al., J. Exp. Med. 166:1351 -1361 (1987)). Alternatively, non-radioactive assays methods may be employed (see, for example, ACTITMnon-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, CA; and CytoTox 96® non-radioactive cytotoxicity assay (Promega, Madison, Wl). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc. Nat’l Acad. Sci. USA 95:652- 656 (1998). C1 q binding assays may also be carried out to confirm that the antibody is unable to bind C1q and hence lacks CDC activity. See, e.g., C1 q and C3c binding ELISA in WO 2006 / 029879 and WO 2005 / 100402. To assess complement activation, a CDCassay may be performed (see, for example, Gazzano-Santoro et aL, J. Immunol. Methods 202:163 (1996); Cragg, M.S. et al., Blood 101 :1045-1052 (2003); and Cragg, M.S. and M.J. Glennie, Blood 103:2738-2743 (2004)). FcRn binding and in vivo clearance / half-life determinations can also be performed using methods known in the art (see, e.g., Petkova, S.B. et aL, Int’l. Immunol. 18(12):1759-1769 (2006); WO 2013 / 120929 Al).

[0279] Antibodies with reduced effector function include those with substitution of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 (U.S. Patent No. 6,737,056). Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called “DANA” Fc mutant with substitution of residues 265 and 297 to alanine (US Patent No. 7,332,581 ). For example, an antibody variant may comprise an Fc region with one or more amino acid substitutions which diminish FcyR binding, e.g., substitutions at positions 234 and 235 of the Fc region (EU numbering of residues). For example, the substitutions are L234A and L235A (LALA) (See, e.g., WO 2012 / 130831 );. The substitutions may additionally include substitution of the proline residue at position 329, such as a P329G mutation to disable binding to FcR . Further, alterations may be made in the Fc region that result in altered (i.e., diminished) C1 q binding and / or Complement Dependent Cytotoxicity (CDC), e.g., as described in US Patent No. 6,194,551 , WO 99 / 51642, and Idusogie et al. J. Immunol. 164: 4178-4184 (2000).

[0280] In some aspects, the Fc region includes mutations to the complement (C1q) and / or to Fc gamma receptor (FcyR) binding sites. In some aspects, such mutations can render the fusion protein incapable of antibody directed cytotoxicity (ADCC) and complement directed cytotoxicity (CDC).

[0281] The Fc region as used in the context of the present invention does not trigger cytotoxicity such as antibody-dependent cellular cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC).

[0282] The term “Fc region” also includes native sequence Fc regions and variant Fc regions. The Fc region may include the carboxyl-terminus of the heavy chain. Antibodies produced by host cells may undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain. Therefore, an antibody produced by a host cell by expression of a specific nucleic acid molecule encoding a full-length heavy chain may include the full-length heavy chain, or it mayinclude a cleaved variant of the full-length heavy chain. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991. Amino acid sequence variants of the Fc region of an antibody may be contemplated. Amino acid sequence variants of an Fc region of an antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and / or insertions into and / or substitutions of residues within the amino acid sequences of the Fc region of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., inducing or supporting an immunostimulatory response.

[0283] The Fc region of the antibody may be an Fc region of any of the classes of antibody, such as IgA, IgD, IgE, IgG, and IgM. The “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. 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., lgG1 , lgG2, lgG3, lgG4, lgA1 , and lgA2. Accordingly, as used in the context of the present invention, the antibody may be an Fc region of an IgG. For example, the Fc region of the antibody may be an Fc region of an IgG 1 , an lgG2, an lgG2b, an lgG3 or an lgG4. In some aspects, the fusion protein of the present invention comprises an IgG of an Fc region of an antibody. In the context of the present invention, the Fc region of the antibody is an Fc region of an IgG, preferably lgG1 .

[0284] In preferred embodiments, the fusion proteins disclosed herein may incorporate Fc variants that improve FcRn binding. Such variants may enhance the in vivo pharmacokinetic properties of proteins described herein. Preferred variants that increase binding to FcRn and / or improve pharmacokinetic properties include but are not limited to substitutions at positions 259, 308, 428, and 434, including but not limited to for example 259I, 308F, 428L, 428M, 434S, 434H, 434F, 434Y, and 434M (U.S. Ser. No. 12 / 341 ,769, filed Dec. 22, 2008, entitled “Fc Variants with Altered Binding to FcRn”, entirely incorporated by reference). Other variants that increase Fc binding to FcRn include but are not limited to: 250E, 250Q, 428L, 428F, 250Q / 428L (Hinton et al., 2004, J. Biol. Chem. 279(8): 6213-6216, Hinton et al. 2006 Journal of Immunology 176:346-356), 256A, 272A,286A, 305A, 307A, 307Q, 31 1 A, 312A, 376A, 378Q, 380A, 382A, 434A (Shields et al, Journal of Biological Chemistry, 2001 , 276(9):6591 -6604, entirely incorporated by reference), 252F, 252T, 252Y, 252W, 254T, 256S, 256R, 256Q, 256E, 256D, 256T, 309P, 31 1S, 433R, 433S, 433I, 433P, 433Q, 434H, 434F, 434Y, 252Y / 254T / 256E, 433K / 434F / 436H, 308T / 309P / 311 S (dall Acqua et al. Journal of Immunology, 2002, 169:5171 -5180, Dall'Acqua et al., 2006, Journal of Biological Chemistry 281 :23514- 23524, entirely incorporated by reference). Other modifications for modulating FcRn binding are described in Yeung et al., 2010, J Immunol, 182:7663-7671 .

[0285] Other Fc modifications for use in the present invention include variants that reduce or ablate binding to FcyRs and / or complement proteins, thereby reducing or ablating Fc-mediated effector functions such as ADCC, ADCP, and CDC. Such variants are also referred to herein as “knockout variants” or “KO variants”. Variants that reduce binding to FcyRs and complement are useful for reducing unwanted interactions mediated by the Fc region and for tuning the selectivity of the proteins herein. Preferred knockout variants are described in US 2008-0242845 A1 , published on Oct. 2, 2008, entitled “Fc Variants with Optimized Properties, expressly incorporated by reference herein. Preferred modifications include but are not limited substitutions, insertions, and deletions at positions 234, 235, 236, 237, 267, 269, 325, and 328, wherein numbering is according to the EU index. Preferred substitutions include but are not limited to 234G, 235G, 236R, 237K, 267R, 269R, 325L, and 328R, wherein numbering is according to the EU index. A preferred variant comprises 236R / 328R. Variants may be used in the context of any IgG isotype or IgG isotype Fc region, including but not limited to human IgG 1 , lgG2, lgG3, and / or lgG4. Preferred IgG Fc regions for reducing FcyR and complement binding and reducing Fc-mediated effector functions are lgG2 and lgG4 Fc regions. Hybrid isotypes may also be useful, for example hybrid lgG1 / lgG2 isotypes as described in U.S. Ser. No. 11 / 256,060. Other modifications for reducing FcyR and complement interactions include but are not limited to substitutions 297A, 234A, 235A, 237A, 318A, 228P, 236E, 268Q, 309L, 330S, 331 S, 220S, 226S, 229S, 238S, 233P, and 234V, as well as removal of the glycosylation at position 297 by mutational or enzymatic means or by production in organisms such as bacteria that do not glycosylate proteins. These and other modifications are reviewed in Strohl, 2009, Current Opinion in Biotechnology 20:685-691 , incorporated by reference in its entirety.

[0286] In certain embodiments, particularly in accordance with the second aspect of the invention, it is desirable to utilise Fc regions of antibodies that retain the ability to homodimerise. Such Fc sequences will be known to the skilled person. For example, in the interface of two lgG1 CH3 domains, there are at least 16 residues in each chain contributing to hydrophobic interactions (eg L351 , T366, T / L368, P395, F405, Y407, and K409) involved in homodimeric interactions.

[0287] In alternative embodiments, Fc modifications that improve binding to FcyRs and / or complement may also find use in the proteins of the invention. Such Fc variants may enhance Fc-mediated effector functions such as ADCC, ADCP, and / or CDC. Preferred modifications for improving FcyR and complement binding are described in US 2006-0024298 A1 , published on Feb. 2, 2006, and US 2006-0235208 A1 , published on Oct. 19, 2006, expressly incorporated herein by reference. Preferred modifications comprise a substitution at a position selected from the group consisting of 236, 239, 268, 324, and 332, wherein numbering is according to the EU index. Preferred substitutions include but are not limited to 236A, 239D, 239E, 268D, 267E, 268E, 268F, 324T, 332D, and 332E. Preferred variants include but are not limited to 239D / 332E, 236A / 332E, 236A / 239D / 332E, 268F / 324T, 267E / 268F, 267E / 324T, and 267E / 268F / 324T. Other modifications for enhancing FcyR and complement interactions include but are not limited to substitutions 298A, 333A, 334A, 326A, 2471 , 339D, 339Q, 280H, 290S, 298D, 298V, 243L, 292P, 300L, 396L, 305I, and 396L. These and other modifications are reviewed in Strohl, 2009, ibid.

[0288] In one embodiment, the proteins disclosed herein may incorporate Fc variants that enhance affinity for an inhibitory receptor FcyRllb. Such variants may provide the proteins herein with immunomodulatory activities related to FcyRllb+ cells, including for example B cells and monocytes. In one embodiment, the Fc variants provide selectively enhanced affinity to FcyRllb relative to one or more activating receptors. Modifications for altering binding to FcyRllb are described in U.S. Ser. No. 12 / 156,183, filed May 30, 2008, entitled “Methods and Compositions for Inhibiting CD32b Expressing Cells”, herein expressly incorporated by reference. In particular, Fc variants that improve binding to FcyRllb may include one or more modifications at a position selected from the group consisting of 234, 235, 236, 237, 239, 266, 267, 268, 325, 326, 327, 328, and 332, according to the EU index. Preferable substitutions for enhancing FcyRllb affinity include but are not limited to 234D, 234E, 234W, 235D, 235F, 235R, 235Y, 236D, 236N, 237D,237N, 239D, 239E, 266M, 267D, 267E, 268D, 268E, 327D, 327E, 328F, 328W, 328Y, and 332E. More preferably, substitutions include but are not limited to 235Y, 236D, 239D, 266M, 267E, 268D, 268E, 328F, 328W, and 328Y. Preferred Fc variants for enhancing binding to FcyRllb include but are not limited to 235Y / 267E, 236D / 267E, 239D / 268D, 239D / 267E, 267E / 268D, 267E / 268E, and 267E / 328F.

[0289] Fc-fusion proteins described herein can incorporate Fc modifications in the context of any IgG isotype or IgG isotype Fc region, including but not limited to human lgG1 , lgG2, lgG3, and / or lgG4. The IgG isotype may be selected such as to alter FcyR- and / or complement- mediated effector function(s). Hybrid IgG isotypes may also be useful. For example, U.S. Ser. No. 11 / 256,060 describes a number of hybrid IgG 1 / lgG2 constant regions that may find use in the particular invention. In some embodiments of the invention, CTLA4-lg fusion proteins may comprise means for isotypic modifications, that is, modifications in a parent IgG to the amino acid type in an alternate IgG. For example, an lgG1 / lgG3 hybrid variant may be constructed by a substitutional means for substituting IgG 1 positions in the CH2 and / or CH3 region with the amino acids from lgG3 at positions where the two isotypes differ. Thus, a hybrid variant IgG antibody may be constructed that comprises one or more substitutional means, e.g., 274Q, 276K, 300F, 339T, 356E, 358M, 384S, 392N, 397M, 422I, 435R, and 436F. In other embodiments of the invention, an lgG1 / lgG2 hybrid variant may be constructed by a substitutional means for substituting lgG2 positions in the CH2 and / or CH3 region with amino acids from IgG 1 at positions where the two isotypes differ. Thus, a hybrid variant IgG antibody may be constructed that comprises one or more substitutional means, e.g., one or more of the following amino acid substitutions: 233E, 234L, 235L, -236G (referring to an insertion of a glycine at position 236), and 327A.

[0290] The skilled person will be familiar with standard techniques for designing a bispecific molecule as described herein, including the use of recombinant techniques to ensure the proper dimerisation of non-identical Fc fusion proteins (ie for forcing a pairing of a light chain polypeptide with its correct heavy chain counterpart). Examples of such techniques include the use of so-called “CrossMab” and “DuetMab” systems, such as described in Mazor et al., (2015) mAbs, 7:377-389 and Klein et al., (2016) mAbs, 8:1010- 1020, incorporated herein by reference. These references discuss techniques for enabling the correct association of generic light chains using immunoglobulin domain crossover (CrossMAb technology), which can be combined with approaches enablingcorrect heavy chain association such as knob-into-holes (KIH) (Ridgway et al., (1996), Protein Eng, 9: 617-621 ) technology or electrostatic steering. WO 2009 / 080251 , WO 2009 / 080252, WO 2009 / 080253, WO 2009 / 080254 and Schaefer, W. et al, PNAS, 108 (2011 ) 11187-1191 disclose methods for obtaining bivalent, bispecific IgG antibodies with a domain crossover. WO 2010 / 145792 discloses methods for obtaining tetravalent antigen binding proteins with a domain crossover. The multispecific antibodies with a VH / VL replacement / exchange in one binding site to prevent light chain mispairing (CrossMab VHA L), which are described in WO 2009 / 080252 (see also Schaefer, W. et al, PNAS, 108 (2011 ) 1 1 : 187-1191 ), clearly reduce the production of mispaired variants caused by the mismatch of a light chain against a first antigen with the wrong heavy chain against the second antigen (compared to approaches without such domain exchange). The methods disclosed in the aforementioned documents for preventing mispairing of light and heavy chains (and thereby ensuring that the moiety capable of being bound by the exogenous immune cell receptor is on one portion only of the heterodimeric molecules of the invention) are incorporated herein by reference.

[0291] Similarly, the “DuetMab” technology uses knobs-into-holes (KIH) technology for heterodimersiation of two distinct heavy chains and increases the efficiency of cognate heavy and light chain pairing by replacing the native disulphide bond in one of the CH1 - CL interfaces with an engineered disulphide bond.

[0292] It is well within the purview of the skilled person to be able to determine which of KIH, DuetMab, or CrossMab technology to employ in order to generate molecules falling within the scope of the invention.Linkers

[0293] In any embodiment, VH and VL regions of antigen binding domains as described herein may be linked together via a linker. Further, antigen binding fragments of antibodies (such as scFvs) or CTLA4 polypeptides and variants thereof, may be linked to Fc regions via a linker. The following section describes linkers which may be used for joining any polypeptides described herein.

[0294] 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 antigen binding portions. Such linker polypeptides are well known in the art (see e.g., Holliger, P., et al.(1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, R. J., et al. (1994) Structure 2:1121 -1 123). A variety of linkers may find use in some embodiments described herein to covalently link Fc regions to a fusion partner.

[0295] “Linker” herein is also referred to as “linker sequence”, “spacer”, “tethering sequence” or grammatical equivalents thereof. Homo-or hetero-bifunctional linkers as are well known (see, 1994 Pierce Chemical Company catalog, technical section on crosslinkers, pages 155-200, incorporated entirely by reference). A number of strategies may be used to covalently link molecules together. These include, but are not limited to polypeptide linkages between N- and C-termini of proteins or protein domains, linkage via disulfide bonds, and linkage via chemical cross-linking reagents. In one aspect of this embodiment, the linker is a peptide bond, generated by recombinant techniques or peptide synthesis. The linker peptide may predominantly include the following amino acid residues: Gly, Ser, Ala, or Thr. The linker peptide should have a length that is adequate to link two molecules in such a way that they assume the correct conformation relative to one another so that they retain the desired activity. In one embodiment, the linker is from about 1 to 50 amino acids in length, preferably about 1 to 30 amino acids in length. In one embodiment, linkers of 1 to 20 amino acids in length may be used. Useful linkers include glycine-serine polymers, including for example (GS)n, (GSGGS)n (SEQ ID NO: 343), (GGGGS)n (SEQ ID NO: 344), and (GGGS)n(SEQ ID NO: 345), where n is an integer of at least one, glycine-alanine polymers, alanine-serine polymers, and other flexible linkers. Alternatively, a variety of nonproteinaceous polymers, including but not limited to polyethylene glycol (PEG), polypropylene glycol, polyoxyalkylenes, or copolymers of polyethylene glycol and polypropylene glycol, may find use as linkers, that is may find use as linkers The fusion proteins of the invention may comprise a linker region (or spacer) located between the first and second portions.

[0296] In the context of the present invention, the polypeptide comprising or consisting of the amino acid sequence of a CTLA4 variant is fused via a linker at the C-terminus to the Fc region or Fc receptor binding domain.

[0297] A linker is usually a peptide having a length of up to 20 amino acids. The term “linked to” or “fused to” refers to a covalent bond, e g., a peptide bond, formed between two moieties. Accordingly, in the context of the present invention the linker may have a length of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22 amino acids. For example, the herein provided fusion protein may comprise a linker betweenthe polypeptide comprising or consisting of an amino acid sequence of a CLTA4 variant and the Fc region of the antibody, such as between the N-terminus of the Fc regions / FcR binding domains and the C-terminus of the polypeptide. Such linkers have the advantage that they can make it more likely that the different polypeptides of the fusion protein fold independently and behave as expected.

[0298] Thus, in the context of the present invention the polypeptide comprising or consisting of the first and second portions may be comprised in a single-chain multifunctional polypeptide.

[0299] In some aspects, the fusion protein of the present invention includes a peptide linker. The skilled person will be familiar with the design and use of various peptide linkers comprised of various amino acids, and of various lengths, which would be suitable for use as linkers in accordance with the present invention. The linker may comprise various combinations of repeated amino acid sequences.

[0300] The linker may be a flexible linker (such as those comprising repeats of glycine and serine residues), a rigid linker (such as those comprising glutamic acid and lysine residues, flanking alanine repeats) and / or a cleavable linker (such as sequences that are susceptible by protease cleavage). Examples of such linkers are known to the skilled person and are described for example, in Chen et al., (2013) Advanced Drug Delivery Reviews, 65: 1357-1369.

[0301] In some aspects, the peptide linker may include the amino acids glycine and serine in various lengths and combinations. In some aspects, the peptide linker can include the sequence Gly-Gly-Ser (GGS), Gly-Gly-Gly-Ser (GGGS, SEQ ID NO: 345) or Gly-Gly-Gly-Gly-Ser (GGGGS, SEQ ID NO: 344) and variations or repeats thereof. In some aspects, the peptide linker can include the amino acid sequence GGGGGS (a linker of 6 amino acids in length, SEQ ID NO: 346) or even longer. The linker may a series of repeating glycine and serine residues (GS) of different lengths, i.e., (GS)n where n is any number from 1 to 15 or more. For example, the linker may be (GS)s (i.e., GSGSGS, SEQ ID NO: 347) or longer (GS)n (SEQ ID NO: 348) or longer. It will be appreciated that n can be any number including 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or more. Fusion proteins having linkers of such length are included within the scope of the present invention. Similarly, the linker may be a series of repeating glycine residues separated by serine residues. Forexample (GGGGS)s (i.e., the linker may comprise the amino acid sequence GGGGSGGGGSGGGGS, (G4S)a, SEQ ID NO: 349) and variations thereof.

[0302] The peptide linker may consist of a series of repeats of Thr-Pro (TP) comprising one or more additional amino acids N and C terminal to the repeat sequence. For example, the linker may comprise or consist of the sequence GTPTPTPTPTGEF (SEQ ID NO: 350, also known as the TP5 linker). In further aspects, the linker may be a short and / or alpha-helical rigid linker (e.g. A(EAAAK)3A, SEQ ID NO: 351 ; PAPAP, SEQ ID NO: 352; or a dipeptide such as LE).

[0303] In certain aspects, the linker may be flexible and cleavable. Such linkers preferably comprise one or more recognition sites for a protease to enable cleavage.

[0304] Preferred linkers of the invention comprise sequences from an antibody hinge region. Hinge regions sequences from any antibody isotype may be used, including for example hinge sequences from lgG1 , lgG2, lgG3, and / or lgG4. Linker sequences may also include any sequence of any length of CL / CH1 domain but not all residues of CL / CH1 domain; for example, the first 5-12 amino acid residues of the CL / CH1 domains. Linkers can be derived from immunoglobulin heavy chains of any isotype, including for example Cy1 , Cy2, Cy3, Cy4, Ca1 , Ca2, C5, Cs, and Cp. Linkers can be derived from immunoglobulin light chain, for example CK or CA. Linker sequences may also be derived from other proteins such as Ig-like proteins (e.g. TCR, FcR, KIR), hinge region-derived sequences, and other natural sequences from other proteins.Nucleic acids

[0305] The present invention provides various nucleic acid constructs, or isolated nucleic acids encoding the fusion proteins described herein.

[0306] An "isolated" nucleic acid molecule is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule with which it is ordinarily associated in the natural source. An isolated nucleic acid molecule is other than in the form or setting in which it is found in nature. Isolated nucleic acid molecules therefore are distinguished from the nucleic acid molecule as it exists in natural cells. However, an isolated nucleic acid molecule includes nucleic acid molecules contained in cells that ordinarily express, for example, CTLA4, where, for example, the nucleic acid molecule is in a chromosomal location different from that of natural cells.

[0307] The terms “nucleic acid molecule” and “polynucleotide” are used interchangeably herein and refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Non-limiting examples of polynucleotides include a gene, a gene fragment, messenger RNA (mRNA), cDNA, recombinant polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. A polynucleotide of the invention may be provided in isolated or purified form. A nucleic acid sequence which “encodes” a selected polypeptide is a nucleic acid molecule which is transcribed (in the case of DNA) and translated (in the case of mRNA) into a polypeptide in vivo when placed under the control of appropriate regulatory sequences. The boundaries of the coding sequence are determined by a start codon at the 5' (amino) terminus and a translation stop codon at the 3' (carboxy) terminus. For the purposes of the invention, such nucleic acid sequences can include, but are not limited to, cDNA from viral, prokaryotic or eukaryotic mRNA, genomic sequences from viral or prokaryotic DNA or RNA, and even synthetic DNA sequences. A transcription termination sequence may be located 3' to the coding sequence.

[0308] Polynucleotides of the invention can be synthesised according to methods well known in the art, as described by way of example in Sambrook et al (1989, Molecular Cloning — a laboratory manual; Cold Spring Harbor Press).

[0309] The polynucleotide molecules of the present invention may be provided in the form of an expression cassette which includes control sequences operably linked to the inserted sequence, thus allowing for expression of the polypeptide of the invention in vivo in a targeted subject. These expression cassettes, in turn, are typically provided within vectors (e.g., plasmids or recombinant viral vectors) which are suitable for use as reagents for nucleic acid immunization. Such an expression cassette may be administered directly to a host subject. Alternatively, a vector comprising a polynucleotide of the invention may be administered to a host subject. Preferably the polynucleotide is prepared and / or administered using a genetic vector. A suitable vector may be any vector which is capable of carrying a sufficient amount of genetic information, and allowing expression of a polypeptide of the invention.

[0310] The present invention thus includes expression vectors that comprise such polynucleotide sequences.

[0311] Furthermore, it will be appreciated that the compositions and products of the invention may comprise a mixture of polypeptides and polynucleotides. Accordingly, the invention provides a composition or product as defined herein, wherein in place of any one of the polypeptides is a polynucleotide capable of expressing said polypeptide.

[0312] Expression vectors are routinely constructed in the art of molecular biology and may for example involve the use of plasmid DNA and appropriate initiators, promoters, enhancers and other elements, such as for example polyadenylation signals which may be necessary, and which are positioned in the correct orientation, in order to allow for expression of a peptide of the invention. Other suitable vectors would be apparent to persons skilled in the art.

[0313] Thus, the methods of the present invention include delivering such a vector to a cell and allowing transcription from the vector to occur. Preferably, a polynucleotide of the invention or for use in the invention in a vector is operably linked to a control sequence which is capable of providing for the expression of the coding sequence by the host cell, i.e. the vector is an expression vector.

[0314] “Operably linked” refers to an arrangement of elements wherein the components so described are configured so as to perform their usual function. Thus, a given regulatory sequence, such as a promoter, operably linked to a nucleic acid sequence is capable of effecting the expression of that sequence when the proper enzymes are present. The promoter need not be contiguous with the sequence, so long as it functions to direct the expression thereof. Thus, for example, intervening untranslated yet transcribed sequences can be present between the promoter sequence and the nucleic acid sequence and the promoter sequence can still be considered “operably linked” to the coding sequence.

[0315] A number of expression systems have been described in the art, each of which typically consists of a vector containing a gene or nucleotide sequence of interest operably linked to expression control sequences. These control sequences include transcriptional promoter sequences and transcriptional start and termination sequences. The vectors of the invention may be for example, plasmid, virus or phage vectors provided with an origin of replication, optionally a promoter for the expression of the said polynucleotide and optionally a regulator of the promoter. A “plasmid” is a vector in the form of an extra-chromosomal genetic element. The vectors may contain one or moreselectable marker genes, for example an ampicillin resistance gene in the case of a bacterial plasmid or a resistance gene for a fungal vector. Vectors may be used in vitro, for example for the production of DNA or RNA or used to transfect or transform a host cell, for example, a mammalian host cell. The vectors may also be adapted to be used in vivo, for example to allow in vivo expression of the polypeptide.

[0316] A “promoter” is a nucleotide sequence which initiates and regulates transcription of a polypeptide-encoding polynucleotide. Promoters can include inducible promoters (where expression of a polynucleotide sequence operably linked to the promoter is induced by an analyte, cofactor, regulatory protein, etc.), repressible promoters (where expression of a polynucleotide sequence operably linked to the promoter is repressed by an analyte, cofactor, regulatory protein, etc.), and constitutive promoters. It is intended that the term “promoter” or “control element” includes full-length promoter regions and functional (e.g., controls transcription or translation) segments of these regions.

[0317] As used herein, the term “promoter” is to be taken in its broadest context and includes the transcriptional regulatory sequences of a genomic gene, including the TATA box or initiator element, which is required for accurate transcription initiation, with or without additional regulatory elements (e.g., upstream activating sequences, transcription factor binding sites, enhancers and silencers) that alter expression of a nucleic acid, e.g., in response to a developmental and / or external stimulus, or in a tissue specific manner. In the present context, the term “promoter” is also used to describe a recombinant, synthetic or fusion nucleic acid, or derivative which confers, activates or enhances the expression of a nucleic acid to which it is operably linked. Exemplary promoters can contain additional copies of one or more specific regulatory elements to further enhance expression and / or alter the spatial expression and / or temporal expression of said nucleic acid.

[0318] Exemplary promoters active in mammalian cells include cytomegalovirus immediate early promoter (CMV-IE), human elongation factor 1 -a promoter (EF1 ), small nuclear RNA promoters (U1 a and U1 b), a-myosin heavy chain promoter, Simian virus 40 promoter (SV40), Rous sarcoma virus promoter (RSV), Adenovirus major late promoter, [3-actin promoter; hybrid regulatory element comprising a CMV enhancer / [3-actin promoter or an immunoglobulin promoter or active fragment thereof. Examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1651 ); human embryonic kidney line (293 or 293 cells subcloned for growthin suspension culture; baby hamster kidney cells (BHK, ATCC CCL 10); or Chinese hamster ovary cells (CHO).

[0319] A polynucleotide, expression cassette or vector according to the present invention may additionally comprise a signal peptide sequence. The signal peptide sequence is generally inserted in operable linkage with the promoter such that the signal peptide is expressed and facilitates secretion of a polypeptide encoded by coding sequence also in operable linkage with the promoter.

[0320] Typically, a signal peptide sequence encodes a peptide of 10 to 30 amino acids for example 15 to 20 amino acids. Often the amino acids are predominantly hydrophobic. In a typical situation, a signal peptide targets a growing polypeptide chain bearing the signal peptide to the endoplasmic reticulum of the expressing cell. The signal peptide is cleaved off in the endoplasmic reticulum, allowing for secretion of the polypeptide via the Golgi apparatus. Thus, a peptide of the invention may be provided to an individual by expression from cells within the individual, and secretion from those cells.

[0321] Any appropriate expression vector (e.g., as described in Pouwels et al., Cloning Vectors: A Laboratory Manual (Elsevier, N.Y.: 1985)) and corresponding suitable host can be employed for production of recombinant polypeptides. Expression hosts include, but are not limited to, bacterial species within the genera Escherichia, Bacillus, Pseudomonas, Salmonella, mammalian or insect host cell systems including baculovirus systems (e.g., as described by Luckow et aL, Bio / Technology 6: 47 (1988)), and established cell lines such as the COS-7, C127, 3T3, CHO, HeLa, and BHK cell lines, and the like. The skilled person is aware that the choice of expression host has ramifications for the type of polypeptide produced. For instance, the glycosylation of polypeptides produced in yeast or mammalian cells (e.g., COS-7 cells) will differ from that of polypeptides produced in bacterial cells, such as Escherichia coli.Polypeptides

[0322] “Isolated," when used to describe the various polypeptides disclosed herein, means the polypeptide that has been identified and separated and / or recovered from a component of its natural environment. Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the polypeptide, and may include enzymes, hormones, and other proteinaceousor non-proteinaceous solutes. In preferred embodiments, the polypeptide will be purified (1 ) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (2) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain. Isolated protein includes polypeptide in situ within recombinant cells, since at least one component of the polypeptide natural environment will not be present. Ordinarily, however, isolated polypeptide will be prepared by at least one purification step.

[0323] A "fragment" is a portion of a polypeptide of the present invention that retains substantially similar functional activity or substantially the same biological function or activity as the polypeptide, which can be determined using assays described herein.

[0324] “Percent (%) amino acid sequence identity” or “percent (%) identical” with respect to a polypeptide sequence, i.e. a polypeptide of the invention defined herein, is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific polypeptide of the invention, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity.

[0325] Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms (non-limiting examples described below) needed to achieve maximal alignment over the full-length of the sequences being compared. When amino acid sequences are aligned, the percent amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain percent amino acid sequence identity to, with, or against a given amino acid sequence B) can be calculated as: percent amino acid sequence identity = X / Y100, where X is the number of amino acid residues scored as identical matches by the sequence alignment program's or algorithm's alignment of A and B and Y is the total number of amino acid residues in B. If the length of amino acid sequence A is not equal to the length of amino acid sequence B, the percent amino acid sequence identity of A to B will not equal the percent amino acid sequence identity of B to A.

[0326] In calculating percent identity, typically exact matches are counted. The determination of percent identity between two sequences can be accomplished using amathematical algorithm. A nonlimiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul (1990) Proc. Natl. Acad. Sci. USA 87:2264, modified as in Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877. Such an algorithm is incorporated into the BLASTN and BLASTX programs of Altschul et al. (1990) J. Mol. Biol. 215:403. To obtain gapped alignments for comparison purposes, Gapped BLAST (in BLAST 2.0) can be utilized as described in Altschul et al. (1997) Nucleic Acids Res. 25:3389. Alternatively, PSI-Blast can be used to perform an iterated search that detects distant relationships between molecules. See Altschul et al. (1997) supra. When utilizing BLAST, Gapped BLAST, and PSI-Blast programs, the default parameters of the respective programs (e.g., BLASTX and BLASTN) can be used. Alignment may also be performed manually by inspection. Another non- limiting example of a mathematical algorithm utilized for the comparison of sequences is the ClustalW algorithm (Higgins et al. (1994) Nucleic Acids Res. 22:4673- 4680). ClustalW compares sequences and aligns the entirety of the amino acid or DNA sequence, and thus can provide data about the sequence conservation of the entire amino acid sequence. The ClustalW algorithm is used in several commercially available DNA / amino acid analysis software packages, such as the ALIGNX module of the Vector NTI Program Suite (Invitrogen Corporation, Carlsbad, CA). After alignment of amino acid sequences with ClustalW, the percent amino acid identity can be assessed. A non-limiting example of a software program useful for analysis of ClustalW alignments is GENEDOC™ or JalView (http: / / www.jalview.org / ). GENEDOC™ allows assessment of amino acid (or DNA) similarity and identity between multiple proteins. Another nonlimiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller (1988) CABIOS 4:11 -17. Such an algorithm is incorporated into the ALIGN program (version 2.0), which is part of the GCG Wisconsin Genetics Software Package, Version 10 (available from Accelrys, Inc., 9685 Scranton Rd., San Diego, CA, USA). When utilizing the ALIGN program for comparing amino acid sequences, a PAM 120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used.

[0327] The polypeptide desirably comprises an amino end and a carboxyl end. The polypeptide can comprise D-amino acids, L-amino acids or a mixture of D- and L-amino acids. The D-form of the amino acids, however, is particularly preferred since a polypeptide comprised of D-amino acids is expected to have a greater retention of its biological activity in vivo.

[0328] The polypeptide can be prepared by any of a number of conventional techniques. The polypeptide can be isolated or purified from a naturally occurring source or from a recombinant source. Recombinant production is preferred. For instance, in the case of recombinant polypeptides, a DNA fragment encoding a desired peptide can be subcloned into an appropriate vector using well-known molecular genetic techniques (see, e.g., Maniatis et al., Molecular Cloning: A Laboratory Manual, 2nd ed. (Cold Spring Harbor Laboratory, 1982); Sambrook et al., Molecular Cloning A Laboratory Manual, 2nd ed. (Cold Spring Harbor Laboratory, 1989). The fragment can be transcribed and the polypeptide subsequently translated in vitro. Commercially available kits also can be employed (e.g., such as manufactured by Clontech, Palo Alto, Calif.; Amersham Pharmacia Biotech Inc., Piscataway, N.J.; InVitrogen, Carlsbad, Calif., and the like). The polymerase chain reaction optionally can be employed in the manipulation of nucleic acids.

[0329] The term "conservative substitution" as used herein, refers to the replacement of an amino acid present in the native sequence in the peptide with a naturally or non- naturally occurring amino acid or a peptidomimetic having similar steric properties. Where the side-chain of the native amino acid to be replaced is either polar or hydrophobic, the conservative substitution should be with a naturally occurring amino acid, a non- naturally occurring amino acid or with a peptidomimetic moiety which is also polar or hydrophobic (in addition to having the same steric properties as the side-chain of the replaced amino acid).

[0330] Conservative amino acid substitution tables providing functionally similar amino acids are well known to one of ordinary skill in the art. The following six groups are examples of amino acids that may be considered to be conservative substitutions for one another:

[0331] 1 ) Alanine (A), Serine (S), Threonine (T);

[0332] 2) Aspartic acid (D), Glutamic acid (E);

[0333] 3) Asparagine (N), Glutamine (Q);

[0334] 4) Arginine (R), Lysine (K);

[0335] 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); and

[0336] 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W).

[0337] As naturally occurring amino acids are typically grouped according to their properties, conservative substitutions by naturally occurring amino acids can be determined bearing in mind the fact that replacement of charged amino acids by sterically similar non-charged amino acids are considered as conservative substitutions. For producing conservative substitutions by non-naturally occurring amino acids it is also possible to use amino acid analogs (synthetic amino acids) well known in the art. A peptidomimetic of the naturally occurring amino acid is well documented in the literature known to the skilled person and non-natural or unnatural amino acids are described further below. When affecting conservative substitutions, the substituting amino acid should have the same or a similar functional group in the side chain as the original amino acid.

[0338] The phrase "non-conservative substitution" or a “non-conservative residue” as used herein refers to replacement of the amino acid as present in the parent sequence by another naturally or non-naturally occurring amino acid, having different electrochemical and / or steric properties. Thus, the side chain of the substituting amino acid can be significantly larger (or smaller) than the side chain of the native amino acid being substituted and / or can have functional groups with significantly different electronic properties than the amino acid being substituted. Examples of non-conservative substitutions of this type include the substitution of phenylalanine or cycohexylmethyl glycine for alanine, isoleucine for glycine, or -NH-CH[(-CH2)5-COOH]-CO- for aspartic acid. Non-conservative substitution includes any mutation that is not considered conservative.

[0339] A non-conservative amino acid substitution can result from changes in: (a) the structure of the amino acid backbone in the area of the substitution; (b) the charge or hydrophobicity of the amino acid; or (c) the bulk of an amino acid side chain. Substitutions generally expected to produce the greatest changes in protein properties are those in which: (a) a hydrophilic residue is substituted for (or by) a hydrophobic residue; (b) a proline is substituted for (or by) any other residue; (c) a residue having a bulky side chain, e.g., phenylalanine, is substituted for (or by) one not having a side chain, e.g., glycine; or (d) a residue having an electropositive side chain, e.g., lysyl, arginyl, or histadyl, is substituted for (or by) an electronegative residue, e.g., glutamyl or aspartyl.

[0340] Alterations of the native amino acid sequence to produce mutant polypeptides, such as by insertion, deletion and / or substitution, can be done by a variety of means known to those skilled in the art. For instance, site-specific mutations can be introduced by ligating into an expression vector a synthesized oligonucleotide comprising the modified site. Alternately, oligonucleotide-directed site-specific mutagenesis procedures can be used, such as disclosed in Walder et al., Gene 42: 133 (1986); Bauer et al., Gene 37: 73 (1985); Craik, Biotechniques, 12-19 (January 1995); and U.S. Pat. Nos. 4,518,584 and 4,737,462. A preferred means for introducing mutations is the QuikChange Site- Directed Mutagenesis Kit (Stratagene, LaJolla, Calif.).

[0341] The terms "N-terminal" and "C-terminal" are used herein to designate the relative position of any amino acid sequence or polypeptide domain or structure to which they are applied. The relative positioning will be apparent from the context. That is, an "N-terminal" feature will be located at least closer to the N-terminus of the polypeptide molecule than another feature discussed in the same context (the other feature possible referred to as "C-terminal" to the first feature). Similarly, the terms "5'-" and "3'-" can be used herein to designate relative positions of features of polynucleotides.

[0342] A recombinant polypeptide made in accordance with the methods of the present invention may also be modified by, conjugated or fused to another moiety to facilitate purification of the polypeptides, or for use in immunoassays using methods known in the art. For example, a polypeptide of the invention may be modified by glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting / blocking groups, proteolytic cleavage, etc.

[0343] Modifications contemplated herein include, but are not limited to, modification to side chains, incorporating of unnatural amino acids and / or their derivatives during polypeptide synthesis and the use of crosslinkers and other methods which impose conformational constraints on the polypeptides of the invention. Any modification, including post-translational modification, that introduces flexibility or destabilised the homodimerisation interface of the CTLA4 molecule, but wherein the molecule retains its ability to form a dimer, is contemplated herein. An example includes modification incorporated by click chemistry as known in the art. Exemplary modifications include glycosylation.

[0344] Examples of side chain modifications contemplated by the present invention include modifications of amino groups such as by reductive alkylation by reaction with an aldehyde followed by reduction with NaBF ; amidination with methylacetimidate; acylation with acetic anhydride; carbamoylation of amino groups with cyanate; trinitrobenzylation of amino groups with 2, 4, 6-trinitrobenzene sulphonic acid (TNBS); acylation of amino groups with succinic anhydride and tetrahydrophthalic anhydride; and pyridoxylation of lysine with pyridoxal-5-phosphate followed by reduction with NaBH4.

[0345] The guanidine group of arginine residues may be modified by the formation of heterocyclic condensation products with reagents such as 2,3-butanedione, phenylglyoxal and glyoxal.

[0346] The carboxyl group may be modified by carbodiimide activation via O- acylisourea formation followed by subsequent derivatisation, for example, to a corresponding amide.

[0347] Sulphydryl groups may be modified by methods such as carboxymethylation with iodoacetic acid or iodoacetamide; performic acid oxidation to cysteic acid; formation of a mixed disulphides with other thiol compounds; reaction with maleimide, maleic anhydride or other substituted maleimide; formation of mercurial derivatives using 4- chloromercuribenzoate, 4-chloromercuriphenylsulphonic acid, phenylmercury chloride, 2- chloromercuri-4-nitrophenol and other mercurials; carbamoylation with cyanate at alkaline pH.

[0348] Tryptophan residues may be modified by, for example, oxidation with N- bromosuccinimide or alkylation of the indole ring with 2-hydroxy-5-nitrobenzyl bromide or sulphenyl halides. Tyrosine residues on the other hand, may be altered by nitration with tetranitromethane to form a 3-nitrotyrosine derivative.

[0349] Modification of the imidazole ring of a histidine residue may be accomplished by alkylation with iodoacetic acid derivatives or N-carboethoxylation with diethylpyrocarbonate.

[0350] Examples of incorporating unnatural amino acids and derivatives during protein synthesis include, but are not limited to, use of norleucine, 4-amino butyric acid, 4-amino- 3-hydroxy-5-phenylpentanoic acid, 6-aminohexanoic acid, t-butylglycine, norvaline, phenylglycine, ornithine, sarcosine, 4-amino-3-hydroxy-6-methylheptanoic acid, 2-thienylalanine and / or D-isomers of amino acids. A list of unnatural amino acids contemplated herein is shown in Table 14.Table 14Non-conventional Code Non-conventional Code amino acid amino acid a-aminobutyric acid Abu L-N-methylalanine Nmala a-amino-a-methylbutyrate Mgabu L-N-methylarginine Nmarg aminocyclopropane- Cpro L-N-methylasparagine Nmasn carboxylate L-N-methylaspartic acid Nmasp aminoisobutyric acid Aib L-N-methylcysteine Nmcys aminonorbornyl- Norb L-N-methylglutamine Nmgln carboxylate L-N-methylglutamic acid Nmglu cyclohexylalanine Chexa L-N-methylhistidine Nmhis cyclopentylalanine Cpen L-N-methylisolleucine NmileD-alanine Dal L-N-methylleucine NmleuD-arginine Darg L-N-methyllysine NmlysD-aspartic acid Dasp L-N-methylmethionine NmmetD-cysteine Deys L-N-methylnorleucine NmnleD-glutamine Dgln L-N-methylnorvaline NmnvaD-glutamic acid Dglu L-N-methylornithine NmornD-histidine Dhis L-N-methylphenylalanine NmpheD-isoleucine Dile L-N-methylproline NmproD-leucine Dleu L-N-methylserine NmserD-lysine Dlys L-N-methylthreonine NmthrD-methionine Dmet L-N-methyltryptophan NmtrpD-ornithine Dorn L-N-methyltyrosine NmtyrD-phenylalanine Dphe L-N-methylvaline NmvalD-proline Dpro L-N-methylethylglycine NmetgD-serine Dser L-N-methyl-t-butylglycine NmtbugD-threonine Dthr L-norleucine NleD-tryptophan Dtrp L-norvaline NvaD-tyrosine Dtyr a-methyl-aminoisobutyrate MaibD-valine Dval a-methyl-y-aminobutyrate MgabuD-a-methylalanine Dmala a-methylcyclohexylalanine MchexaD-a-methylarginine Dmarg a-methylcylcopentylalanine McpenD-a-methylasparagine Dmasn a-methyl-a-napthylalanine ManapD-a-methylaspartate Dmasp a-methylpenicillamine MpenD-a-methylcysteine Dmcys N-(4-aminobutyl)glycine NgluD-a-methylglutamine Dmgln N-(2-aminoethyl)glycine NaegD-a-methylhistidine Dmhis N-(3-aminopropyl)glycine NornD-a-methylisoleucine Dmile N-amino-a-methylbutyrate NmaabuD-a-methylleucine Dmleu a-napthylalanine AnapD-a-methyllysine Dmlys N-benzylglycine NpheD-a-methylmethionine Dmmet N-(2-carbamylethyl)glycine NglnD-a-methylornithine Dmorn N-(carbamylmethyl)glycine NasnD-a-methylphenylalanine Dmphe N-(2-carboxyethyl)glycine NgluD-a-methylproline Dmpro N-(carboxymethyl)glycine NaspD-a-methylserine Dmser N-cyclobutylglycine NcbutD-a-methylthreonine Dmthr N-cycloheptylglycine NchepD-a-methyltryptophan Dmtrp N-cyclohexylglycine NchexD-a-methyltyrosine Dmty N-cyclodecylglycine NcdecD-a-methylvaline Dmval N-cylcododecylglycine NcdodD-N-methylalanine Dnmala N-cyclooctylglycine Neo ctD-N-methylarginine Dnmarg N-cyclopropylglycine NcproD-N-methylasparagine Dnmasn N-cycloundecylglycine NcundD-N-methylaspartate Dnmasp N-(2,2-diphenylethyl)glycine NbhmD-N-methylcysteine Dnmcys N-(3,3-diphenylpropyl)glycine NbheD-N-methylglutamine Dnmgln N-(3-guanidinopropyl)glycine NargD-N-methylglutamate Dnmglu N-(1 -hydroxyethyl)glycine NthrD-N-methylhistidine Dnmhis N-(hydroxyethyl))glycine NserD-N-methylisoleucine Dnmile N-(imidazolylethyl))glycine NhisD-N-methylleucine Dnmleu N-(3-indolylyethyl)glycine NhtrpD-N-methyllysine Dnmlys N-methyl-y-aminobutyrate NmgabuN-methylcyclohexylalanineNmchexa D-N-methylmethionine DnmmetD-N-methylornithine Dnmorn N-methylcyclopentylalanine NmcpenN-methylglycine Nala D-N-methylphenylalanine DnmpheN-methylaminoisobutyrate Nmaib D-N-methylproline DnmproN-(1 -methylpropyl)glycine Nile D-N-methylserine DnmserN-(2-methylpropyl)glycine Nleu D-N-methylthreonine DnmthrD-N-methyltryptophan Dnmtrp N-(1 -methylethyl)glycine NvalD-N-methyltyrosine Dnmtyr N-methyla-napthylalanine NmanapD-N-methylvaline Dnmval N-methylpenicillamine Nmpen y-aminobutyric acid Gabu N-(p-hydroxyphenyl)glycine NhtyrL-t-butylglycine Tbug N-(thiomethyl)glycine NcysL-ethylglycine Etg penicillamine PenL-homophenylalanine Hphe L-a-methylalanine MalaL-a-methylarginine Marg L-a-methylasparagine MasnL-a-methylaspartate Masp L-a-methyl-t-butylglycine MtbugL-a-methylcysteine Mcys L-methylethylglycine MetgL-a-methylglutamine Mgln L-a-methylglutamate MgluL-a-methylhistidine Mhis L-a-methylhomophenylalanine MhpheL-a-methylisoleucine Mile N-(2-methylthioethyl)glycine NmetL-a-methylleucine Mleu L-a-methyllysine MlysL-a-methylmethionine Mmet L-a-methylnorleucine MnleL-a-methylnorvaline Mnva L-a-methylornithine MornL-a-methylphenylalanine Mphe L-a-methylproline MproL-a-methylserine Mser L-a-methylthreonine MthrL-a-methyltryptophan Mtrp L-a-methyltyrosine MtyrL-a-methylvaline Mval L-N-methylhomophenylalanine NmhpheN-(N-(2,2-diphenylethyl) Nnbhm N-(N-(3,3-diphenylpropyl) Nnbhe carbamylmethyl)glycine carbamylmethyl)glycine1 -carboxy-1 -(2,2-diphenyl-Nmbc ethylamino)cyclopropane

[0351] Crosslinkers can be used, for example, to stabilise 3D conformations, using homo-bifunctional crosslinkers such as the bifunctional imido esters having (CH2)n spacer groups with n=1 to n=6, glutaraldehyde, N-hydroxysuccinimide esters and heterobifunctional reagents which usually contain an amino-reactive moiety such as N- hydroxysuccinimide and another group specific-reactive moiety.Cell culture

[0352] Persons skilled in the art will be familiar with standard methods for transfecting host cells, such as mammalian cells, with a nucleic acid vector and culturing the host cell in suitable conditions for expressing genes encoded by the vector. Representative methods for transfection and culturing of mammalian cells to produce recombinant protein are described, for example in Ausubel et al., (editors), Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley-lnterscience (1988, including all updates until present) or Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press (1989).

[0353] Means for introducing the isolated nucleic acid, vector or expression construct comprising same into a cell for expression are known to those skilled in the art. The technique used for a given cell depends on the known successful techniques. Means for introducing recombinant DNA into cells include microinjection, transfection mediated by DEAE-dextran, transfection mediated by liposomes such as by using lipofectamine (Gibco, MD, USA) and / or cellfectin (Gibco, MD, USA), PEG-mediated DNA uptake, electroporation and microparticle bombardment such as by using DNA-coated tungsten or gold particles (Agracetus Inc., Wl, USA) amongst others.

[0354] The host cells used in accordance with the present invention may be cultured in a variety of media, depending on the cell type used. Commercially available media such as Ham's FIO (Sigma), Minimal Essential Medium ((MEM), (Sigma), RPMI-1640 (Sigma), and Dulbecco's Modified Eagle's Medium ((DMEM), Sigma) are suitable for culturing mammalian cells. Media for culturing other cell types discussed herein are known in the art.

[0355] Moreover, the skilled person will be familiar with methods for purifying expressed recombinant protein from cell culture media, including using size exclusion and affinity chromatography methods, and combinations thereof.

[0356] Where a protein is secreted into culture medium, supernatants from such expression systems can be first concentrated using a commercially available protein concentration filter, for example, an Amicon or Millipore Pellicon ultrafiltration unit. A protease inhibitor such as PMSF may be included in any of the foregoing steps to inhibit proteolysis and antibiotics may be included to prevent the growth of adventitiouscontaminants. Alternatively, or additionally, supernatants can be filtered and / or separated from cells expressing the protein, e.g., using continuous centrifugation.

[0357] The protein prepared from the cells can be purified using, for example, ion exchange, hydroxyapatite chromatography, hydrophobic interaction chromatography, gel electrophoresis, dialysis, affinity chromatography (e.g., lysine affinity column), or any combination of the foregoing. These methods are known in the art and described, for example in WO99 / 57134 or Ed Harlow and David Lane (editors) Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, (1988).

[0358] The skilled artisan will also be aware that a protein can be modified to include a tag to facilitate purification or detection, e.g., a poly-histidine tag, e.g., a hexahistidine tag, or an influenza virus hemagglutinin (HA) tag, or a Simian Virus 5 (V5) tag, or a FLAG tag, or a glutathione S-transferase (GST) tag. The resulting protein is then purified using methods known in the art, such as, affinity purification. For example, a protein comprising a hexa-his tag is purified by contacting a sample comprising the protein with nickel-nitrilotriacetic acid (Ni-NTA) that specifically binds a hexa-his tag immobilized on a solid or semi-solid support, washing the sample to remove unbound protein, and subsequently eluting the bound protein. Alternatively, or in addition a ligand or antibody that binds to a tag is used in an affinity purification method.Compositions

[0359] The proteins of the invention can be provided in a pharmaceutically acceptable composition for administration to an individual in need thereof. For example the fusion proteins made in accordance with the present invention find utility in the treatment of various conditions in which immunosuppression is desired, such as in the treatment of various inflammatory or autoimmune conditions.

[0360] Pharmaceutical compositions are also contemplated wherein a protein as disclosed herein, and one or more additional therapeutically active agents are formulated. Formulations of the proteins disclosed herein are prepared for storage by mixing said protein having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed., 1980, incorporated entirely by reference), in the form of lyophilized formulations or aqueous solutions.

[0361] Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, acetate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl orbenzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3- pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; sweeteners and other flavoring agents; fillers such as microcrystalline cellulose, lactose, corn and other starches; binding agents; additives; coloring agents; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn- protein complexes); and / or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

[0362] In one embodiment, the pharmaceutical composition that comprises the proteins disclosed herein may be in a water-soluble form, such as being present as pharmaceutically acceptable salts, which is meant to include both acid and base addition salts. “Pharmaceutically acceptable acid addition salt” refers to those salts that retain the biological effectiveness of the free bases and that are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Some embodiments include at least one of the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine. The formulations to be used for in vivo administration may be sterile. This is readily accomplished by filtration through sterile filtration membranes or other methods.

[0363] The proteins disclosed herein may also be formulated as immunoliposomes. A liposome is a small vesicle comprising various types of lipids, phospholipids and / or surfactant that is useful for delivery of a therapeutic agent to a mammal. Liposomes containing the proteins are prepared by methods known in the art. The components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes. Particularly useful liposomes can be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG- PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.

[0364] The proteins and other therapeutically active agents may also be entrapped in microcapsules prepared by methods including but not limited to coacervation techniques, interfacial polymerization (for example using hydroxymethylcellulose or...

Claims

CLAIMS1 . A bispecific molecule for binding to CD80 and comprising: a) a first polypeptide for binding to CD80 and inhibiting the binding of PD-L1 to CD80; and b) a second polypeptide for binding to CD80 and inhibiting the binding of CD28 to CD80.

2. The bispecific molecule of claim 1 wherein the first polypeptide is in the form of an antigen binding protein, wherein the protein binds to CD80 and thereby inhibits the binding of PD-L1 thereto.

3. The bispecific molecule of claims 1 or 2, wherein the first polypeptide is capable of binding to or specifically binding to residues of the membrane distal IgV domain of human CD80 (corresponding to residues G34 to A140 of human CD80).

4. The bispecific molecule of claim 3, wherein the first antigen binding protein does not bind to the region or portion of CD80 that is bound by PD-L1 , but upon binding to CD80, prevents or reduces the binding of PD-L1 to CD80.

5. The bispecific molecule of claim 3, wherein the first antigen binding protein is capable of binding to or specifically binding to the region or portion of CD80 that is bound by PD-L1.

6. The bispecific molecule of claim 3, wherein the first antigen binding protein does not inhibit the binding of CD28 to CD80.

7. The bispecific molecule of any one of claims 1 to 6, wherein the first polypeptide comprises an antigen binding protein for binding to CD80 and comprises a CDRH1 , a CDRH2 and / or a CDRH3 of an antigen binding domain having a variable heavy chain (VH) as defined in any one of SEQ ID NOs: 73, 74, 75, 76, 77, 78 or 310; and / or a CDRL1 , a CDRL2 and / or a CDRL3 of an antigen binding domain having a variable light chain (VL) as defined in any one of SEQ ID NOs: 148, 149, 150, 151 , 152, 153 or 311 .

8. The bispecific molecule of any one of the preceding claims wherein the first polypeptide comprises an antigen binding protein comprising:- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 73, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 148;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 74, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 149;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 75, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 150;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 76, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 151 ;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 77, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 152;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 78, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 153; or- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 310 and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 311.

9. The bispecific molecule of any one of claims 1 to 8, wherein the first polypeptide comprises an antigen binding protein comprising:(i) a VH comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 1 (IMGT) or 13 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 2 (IMGT) or 14 or 353 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 3 (IMGT) or 15 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(ii) a VH comprising a sequence as set forth in SEQ ID NO: 73 or 77, or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iii) a VL comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 79 (IMGT) or 91 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 80 (IMGT) or 92 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 81 (IMGT or Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%,at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iv) a VL comprising a sequence as set forth in SEQ ID NO: 148 or 152, or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(v) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 1 , a CDR2 comprising a sequence set forth in SEQ ID NO: 2, and a CDR3 comprising a sequence set forth in SEQ ID NO: 3; or comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 13, a CDR2 comprising a sequence set forth in SEQ ID NO: 14 or 353, and a CDR3 comprising a sequence set forth in SEQ ID NO: 15;(vi) a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 79, a CDR2 comprising a sequence set forth in SEQ ID NO: 80 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 81 ; or comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 91 , a CDR2 comprising a sequence set forth in SEQ ID NO: 92 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 81 ;(vii) a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 1 , a CDR2 comprising a sequence as set forth in SEQ ID NO: 2 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 3; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 79, a CDR2 comprising a sequence as set forth in SEQ ID NO: 80 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 81 ; or a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 13, a CDR2 comprising a sequence as set forth in SEQ ID NO: 14 or 353 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 15; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 91 , a CDR2 comprising a sequence as set forth in SEQ ID NO: 92 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 81 ; or(viii) a VH comprising a sequence as set forth in SEQ ID NO: 73 and a VL comprising a sequence set forth in SEQ ID NO: 148; or a VH comprising a sequence as set forth in SEQ ID NO: 77 and a VL comprising a sequence set forth in SEQ ID NO: 152.

10. The bispecific molecule of claim 9 wherein the antigen binding domain further comprises at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 25, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 26, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 27, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 28, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 101 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 102, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 103, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 104, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; or(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 49, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%,at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 50, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 51 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 52, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 124, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 125, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 126, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 127, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; or(I) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 41 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 42, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 43, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%,at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 44, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 105, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 106, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 107, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 108, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; or(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 53, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 54, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 55, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 56, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 128, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 129, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 130, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 131 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

11. The bispecific molecule of claim 9 or 10, wherein the antigen binding protein comprises a variable heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 73 or 77, or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical thereto; and a variable light chain comprising the amino acid sequence as set forth in SEQ ID NO: 148 or 152; or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98 %, or at least about 99% identical thereto; wherein the variable heavy and / or light chains comprise no more than 1 , no more than 2, no more than 3, no more than 4, no more than 5, no more than 6, no more than 7, no more than 8, no more than 9, no more than 10, no more than 11 , no more than 12, no more than 13, no more than 14, no more than 15, no more than 16, no more than 17, no more than 18, no more than 19 or no more than 20 amino acid residue substitutions, deletions, or additions or combination thereof, outside the indicated CDR sequences, and wherein the antigen binding protein retains the ability to bind to CD80.

12. The bispecific molecule of any one of claims 1 to 8, wherein the first polypeptide comprises an antigen binding protein comprising:(i) a VH comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 4 (IMGT) or 16 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 5 (IMGT) or 17 or 354 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 6 or 18 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(ii) a VH comprising a sequence as set forth in SEQ ID NO: 74 or 78, or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iii) a VL comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 82 (IMGT) or 93 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 83 (IMGT) or 94 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 84 (IMGT or Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%,at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iv) a VL comprising a sequence as set forth in SEQ ID NO: 149 or 153, or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(v) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 4, a CDR2 comprising a sequence set forth in SEQ ID NO: 5, and a CDR3 comprising a sequence set forth in SEQ ID NO: 6; or comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 16, a CDR2 comprising a sequence set forth in SEQ ID NO: 17 or 354, and a CDR3 comprising a sequence set forth in SEQ ID NO: 18;(vi) a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 82, a CDR2 comprising a sequence set forth in SEQ ID NO: 83 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 84; or comprising a CDR1 comprising a set forth in SEQ ID NO: 93, a CDR2 comprising a sequence set forth in SEQ ID NO: 94 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 84;(vii) a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 4, a CDR2 comprising a sequence as set forth in SEQ ID NO: 5 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 6; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 82, a CDR2 comprising a sequence as set forth in SEQ ID NO: 83 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 84; or a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 16, a CDR2 comprising a sequence as set forth in SEQ ID NO: 17 or 354 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 18; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 93, a CDR2 comprising a sequence as set forth in SEQ ID NO: 94 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 84; or(viii) a VH comprising a sequence as set forth in SEQ ID NO: 74; and a VL comprising a sequence set forth in SEQ ID NO: 149; or a VH comprising a sequence as set forth in SEQ ID NO: 78; and a VL comprising a sequence set forth in SEQ ID NO: 153.

13. The bispecific molecule of claim 12, wherein the antigen binding domain further comprises at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 29, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 30, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 31 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 32, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 109, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 110, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 111 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 112, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; or(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 57, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%,at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 58, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 59, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 60, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 132, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 133, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 134, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 135, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; or(I) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 45, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 46, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 47, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%,at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 48, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 113, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 114, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 115, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 116, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; or(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 61 , or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 62, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 63, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 64, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 136, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 137, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 138, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 139, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

14. The bispecific molecule of claim 12 or 13 wherein the antigen binding protein comprises a variable heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 74 or 78, or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical thereto; and a variable light chain comprising the amino acid sequence as set forth in SEQ ID NO: 149 or 153; or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98 %, or at least about 99% identical thereto; wherein the variable heavy and / or light chains comprise no more than 1 , no more than 2, no more than 3, no more than 4, no more than 5, no more than 6, no more than 7, no more than 8, no more than 9, no more than 10, no more than 11 , no more than 12, no more than 13, no more than 14, no more than 15, no more than 16, no more than 17, no more than 18, no more than 19 or no more than 20 amino acid residue substitutions, deletions, or additions or combination thereof, outside the indicated CDR sequences, and wherein the antigen binding protein retains the ability to bind to CD80.

15. The bispecific molecule of any one of claims 1 to 8, wherein the first polypeptide comprises an antigen binding protein that comprises, consists essentially of or consists of the amino acid sequence of (in order of N to C terminus or C to N terminus) SEQ IDNOs: 73 and 148; or comprises an antigen binding protein that comprises, consists essentially of or consists of the amino acid sequence of (in order of N to C terminus or C to N terminus) SEQ ID NOs: 77 and 152.

16. The bispecific molecule of any one of claims 1 to 8, wherein the first polypeptide comprises an antigen binding protein that comprises, consists essentially of or consists of the amino acid sequence of (in order of N to C terminus or C to N terminus) SEQ ID NOs: 74 and 149; or comprises an antigen binding protein that comprises, consists essentially of or consists of the amino acid sequence of (in order of N to C terminus or C to N terminus) SEQ ID NOs: 78 and 153.

17. The bispecific molecule of any one of claims 1 to 16, wherein the second polypeptide is in the form of a native binding partner of CD80, or functional homologue or variant of a native binding partner of CD80, that preferably reduces or inhibits or blocks the binding of CD28 to CD80.

18. The bispecific molecule of claim 17, wherein the native binding partner of CD80 is CTLA4 or a fragment or functional derivative thereof.

19. The bispecific molecule of claim 17 or 18 wherein the second polypeptide comprises at least the sequence of the ligand binding domain of a CTLA4 protein, wherein the sequence of the ligand binding domain is common to both the soluble and transmembrane forms of the CTLA4 protein.

20. The bispecific molecule of any one of claims 1 to 19, wherein the second polypeptide comprises or consists of an amino acid sequence of a CTLA4 protein, as set forth herein in any of SEQ ID NOs: 304 to 309, 341 and 342 or a variant thereof that retains the ability to bind to CD80.21 . The bispecific molecule of claim 20, wherein the CTLA4 protein sequence is joined to an Fc region of an antibody, either directly, or via a linker.

22. The bispecific molecule of any one of claims 1 to 21 , wherein the second polypeptide comprises the amino acid sequence of SEQ ID NO: 341 .

23. The bispecific molecule of any one of claims 1 to 22, wherein the second polypeptide is in the form of an antigen binding protein that binds to CD80 and inhibits the binding of CD28 to CD80.

24. The bispecific molecule of any one of claims 1 to 17, wherein the second polypeptide is capable of binding to or specifically binding to residues of the membrane distal IgV domain of human CD80 (corresponding to residues G34 to A140 of human CD80).

25. The bispecific molecule of claim 24, wherein the second antigen binding protein does not bind to the region or portion of CD80 that is bound by CD28, but binding to CD80, prevents or reduces the binding of CD28 to CD8026. The bispecific molecule of claim 24, wherein the second antigen binding protein as described herein is capable of binding to or specifically binding to the region or portion of CD80 that is bound by CD28.

27. The bispecific molecule of claim 24, wherein upon binding to CD80, the second antigen binding protein does not inhibit the binding of PD-L1 to CD80; or wherein the second antigen binding protein inhibits the binding of PD-L1 to CD80 in addition to inhibiting the binding of CD28 to CD80.

28. The bispecific molecule of any one of claims 24 to 27, wherein the second polypeptide comprises an antigen binding protein comprising a CDRH1 , a CDRH2 and / or a CDRH3 of an antigen binding domain having a variable heavy chain as defined in any one of SEQ ID NOs: 230, 231 , 232, 233, 234, 235 or 236; and / or a CDRL1 , a CDRL2 and / or a CDRL3 of an antigen binding domain having a variable light chain as defined in any one of SEQ ID NOs: 297, 298, 299, 300, 301 , 302 or 303.

29. The bispecific molecule of any one of claims 24 to 28, wherein the second polypeptide comprises:- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 231 , and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 298;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 230, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 297;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 232, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 299;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 233, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 300;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 234, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 301 ;- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 235, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 302; or- a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable heavy chain as defined in SEQ ID NO: 236, and a CDR1 , a CDR2 and a CDR3 of an antigen binding domain having a variable light chain as defined in SEQ ID NO: 303.

30. The bispecific molecule of any one of claims 24 to 29, wherein the second polypeptide comprises an antigen binding domain comprising:(i) a VH comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 154 (IMGT) or 169 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 155 (IMGT) or 170 or 356 (Kabat), or a sequence at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 156 (IMGT) or 171 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(ii) a VH comprising a sequence as set forth in SEQ ID NO: 231 or 235, or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iii) a VL comprising a complementarity determining region (CDR) 1 comprising a sequence as set forth in SEQ ID NO: 237 (IMGT) or 249 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; a CDR2 comprising a sequence as set forth in SEQ ID NO: 238 (IMGT) or 250 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto; and a CDR3 comprising a sequence as set forth in SEQ ID NO: 239 (IMGT) or 251 (Kabat), or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(iv) a VL comprising a sequence as set forth in SEQ ID NO: 298 or 302, or a sequence at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto;(v) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 154, a CDR2 comprising a sequence set forth in SEQ ID NO: 155, and a CDR3 comprising a sequence set forth in SEQ ID NO: 156; or comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 169, a CDR2 comprising a sequence set forth in SEQ ID NO: 170 or 356, and a CDR3 comprising a sequence set forth in SEQ ID NO: 171 ;(vi) a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 237, a CDR2 comprising a sequence set forth in SEQ ID NO: 238 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 239; or comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 249, a CDR2 comprising a sequence set forth in SEQ ID NO: 250 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 251 ;(vii) a VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 154, a CDR2 comprising a sequence as set forth in SEQ ID NO: 155 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 156; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 237, a CDR2 comprising a sequence as set forth in SEQ ID NO: 238 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 239; or VH comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 169, a CDR2 comprising a sequence as set forth in SEQ ID NO: 170 or 356 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 171 ; and a VL comprising a CDR1 comprising a sequence as set forth in SEQ ID NO: 249, a CDR2 comprising a sequence as set forth in SEQ ID NO: 250 and a CDR3 comprising a sequence as set forth in SEQ ID NO: 251 ; or(viii) a VH comprising a sequence as set forth in SEQ ID NO: 231 and a VL comprising a sequence set forth in SEQ ID NO: 298; or a VH comprising a sequence as set forth in SEQ ID NO: 235 and a VL comprising a sequence set forth in SEQ ID NO: 302.31 . The bispecific molecule of claim 30, further comprising at least one of:(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 184, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 340, or a sequence at least about 80%, at least 85%, at least90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 185, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 183, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 263, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 260, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 264, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 262, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; or(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 207, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 208, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 209, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 210, or a sequence at least about 80%, at least85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 282, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 283, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 284, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 262, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; or(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 196, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 197, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 198, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 199, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 274, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 275, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 276, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 262, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; or(i) a VH comprising a framework region (FR) 1 comprising an amino acid sequence of SEQ ID NO: 223, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 224, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 225, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 226, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto; and(ii) a VL comprising a FR1 comprising an amino acid sequence of SEQ ID NO: 292, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR2 comprising an amino acid sequence of SEQ ID NO: 293, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto; a FR3 comprising an amino acid sequence of SEQ ID NO: 294, or a sequence at least about 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least99% identical thereto, and a FR4 comprising an amino acid sequence of SEQ ID NO: 262, or a sequence at least about 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% thereto.

32. The bispecific molecule of claim 30 or 31 , wherein the second polypeptide comprises an antigen binding protein comprising a variable heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 231 or 235, or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical thereto; and a variable light chain comprising the amino acid sequence as set forth in SEQ ID NO: 298 or 302; or a sequence at least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98 %, or at least about 99% identical thereto; wherein the variable heavy and / or light chains comprise no more than 1 , no more than 2, no more than 3, no more than 4, no more than 5, no more than 6, no more than 7, no more than 8, no more than 9, no more than 10, no more than 11 , no more than 12, no more than 13, no more than 14, no more than 15, no more than 16, no more than 17, no more than 18, no more than 19 or no more than 20 amino acid residue substitutions, deletions, or additions or combination thereof, outside the indicated CDR sequences, and wherein the antigen binding protein retains the ability to bind to CD80.

33. The bispecific molecule of any one of claims 24 to 32, wherein the second polypeptide comprises an antigen binding domain that comprises, consists essentially of or consists of the amino acid sequence of (in order of N to C terminus or C to N terminus) SEQ ID NOs: 231 and 298.

34. The bispecific molecule of any one of the preceding claims, wherein an antigen binding protein is in the form of:(i) a single domain antibody (sdAb);(ii) a single chain Fv fragment (scFv);(iii) a dimeric scFv (di-scFv); or(iv) one of (i) or (iii) linked to a constant region of an antibody, Fc or a heavy chain constant domain (CH) 2 and / or CH3.

35. The bispecific molecule of any one of the preceding claims, wherein an antigen binding protein is in the form of:(i) a diabody;(ii) a triabody;(iii) a tetrabody;(iv) a Fab;(v) a F(ab’)2;(vi) a Fv;(vii) a bispecific antibody or other form of multispecific antibody (including a BiTE); or(viii) one of (i) to (vii) linked to a constant region of an antibody, Fc or a heavy chain constant domain (CH) 2 and / or CHS.

36. The bispecific molecule of any one of the preceding claims, wherein an antigen binding protein comprises a human constant region such as an IgGi, lgG2, IgGs or lgG4 constant region or mixtures thereof.

37. The bispecific molecule of any one of the preceding claims, wherein the molecule comprises an Fc region that is engineered to:- increase the in vitro or in vivo half-life;- have an increased capacity to induce antibody-dependent cell mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) or complement-dependent cytotoxicity;- reduce effector function; or- increase co-engagement of the molecule.

38. A nucleic acid, or a nucleic acid vector encoding a bispecific molecule of any one of the preceding claims.

39. A cell comprising a vector or a nucleic acid of claim 38.

40. A pharmaceutical composition comprising a bispecific molecule of any one of claims 1 to 37, and a pharmaceutically acceptable carrier, diluent or excipient.41 . A kit or article of manufacture comprising a bispecific molecule of any one of claims 1 to 37, optionally with instructions for the use thereof.

42. A method of treating an inflammatory disorder in a subject in need thereof, the method comprising administering to said subject, a bispecific molecule of any one of claims 1 to 37, or a pharmaceutical composition of claim 40, thereby treating an inflammatory disorder in the subject.

43. Use of a bispecific molecule of any one of claims 1 to 37 in the manufacture of a medicament for the treatment of an inflammatory disorder or a condition or disorder requiring immunosuppression in a subject.

44. The method or use of claims 42 or 43, wherein the inflammatory disorder or condition or disorder requiring immunosuppression is selected from Crohn's disease, systemic lupus erythematosus (SLE), lupus nephritis, psoriatic arthritis, psoriasis, rheumatoid arthritis, ulcerative colitis, transplant rejection and / or Graft-versus-host disease (GvHD).

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