Bispecific polypeptides targeting interleukin 1 beta and type ii collagen and methods of using the same

Abstract

The present disclosure provides bispecific polypeptides comprising at least one first immunoglobulin single variable domain that specifically binds to Interleukin 1 Beta and at least one second immunoglobulin single variable domain that specifically binds to Type II Collagen. The disclosure further provides compositions comprising the bispecific polypeptides and methods of using the same for the treatment of an inflammatory disease or disorder.

Description

Attorney Docket: AVT-001WOBISPECIFIC POLYPEPTIDES TARGETING INTERLEUKIN 1 BETA AND TYPE II COLLAGEN AND METHODS OF USING THE SAMECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U. S. Provisional Application No. 63 / 752131, filed on January 31, 2025, and U. S. Provisional Application No, 63 / 770515, filed on March 12, 2025, the contents of which are hereby incorporated by reference herein in their entirety.SEQUENCE LISTING

[0002] This application contains a Sequence Listing which has been submitted electronically in XML format. The Sequence Listing XML is incorporated herein by reference in its entirety. The XML file, created on March 13, 2025, is named “AVT-001WO_SL.xml” and is 6,129,270 bytes in size.BACKGROUND

[0003] Osteoarthritis is a highly disabling rheumatic disease characterized by aberrant inflammation, chronic pain, and destructive joint pathology. Chronic pain drives approximately 50% of patients with osteoarthritis of the knee to disability and / or total joint replacements (TJR), and approximately 44% of these patients live with chronic pain even after TJR, Current therapeutic modalities largely treat the symptoms of the disease, without addressing the root cause. Therefore, new therapies are needed for treatment of osteoarthritis.

[0004] Gout is precipitation of uric acid crystals into tissue, usually in and around joints, most often causing recurrent acute or chronic arthritis. About 1-7% of the general population suffer from gout, and about 2% of those patients experience refractory' gout. Currently available treatments focus on treatment of symptoms, rather than the root cause of disease, and often require daily injections of therapeutic agents. Tire daily dosing of injectable medications is generally undesirable and may result in problems with patient compliance, thereby decreasing effectiveness of this treatment modality / or limiting its desirability. Thus, there remains a need for effective means to treat gout, particularly refractory' gout.

[0005] Uveitis is an ocular disease characterized by inflammation of the uvea surrounding the iris, ciliary body, and choroid, and can be caused by a bacterial or viral infection of the eye (infectious uveitis) or can result from injury or disease. Treatments for typical ocular inflammation target the inflammatory response. Anti-inflammatoty steroid preparations such 1 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOas the corticosteroids, prednisolone and dexamethasone are drugs of choice in the treatment of uveitis. Other treatments for eye inflammation include immunomodulatory agents, such as cyclosporine, tacrolimus and sirolimus. However, the use of steroids and other immunomodulatory agents is complicated by a large number of severe side effects. Thus, there remains a need for effective means to treat uveitis, particularly noninfectious uveitis.SUMMARY OF THE DISCLOSURE

[0006] Disclosed herein, in certain embodiments, is a bispecific polypeptide, comprising: (a) at least one first immunoglobulin single variable domain (ISVD), wherein the first ISVD specifically binds to Interleukin 1 Beta (IL-1 P); and (b) at least one second ISVD, wherein tire second ISVD specifically binds to Type II Collagen (Col2).

[0007] In certain embodiments, the bispecific polypeptide comprises two second ISVDs that specifically bind to Col2. In certain embodiments, the bispecific polypeptide comprises one first ISVD that specifically binds to IL-1 and two second ISVDs that specifically bind to Col2.

[0008] In certain embodiments, the first ISVD and the second ISVD are each independently aVHH.

[0009] In certain embodiments, the first ISVD comprises a complementarity determining region 1 (CDR1) comprising an amino acid sequence of any one of SEQ ID NOs: 2155-2327 and 6863-6867, a CDR2 comprising an amino acid sequence of any one of SEQ ID NOs: 2501-2673 and and 6873-6877, and a CDR3 comprising an amino acid sequence of any one of SEQ ID NOs: 2847-3019 and and 6883-6887.

[0010] In certain embodiments, the first ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 2045, a CDR2 comprising an amino acid sequence of SEQ ID NO: 2391, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 2737.

[0011] In certain embodiments, the first ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 2046, a CDR2 comprising an amino acid sequence of SEQ ID NO: 2392, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 2738.

[0012] In certain embodiments, the first ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 2047, a CDR2 comprising an amino acid sequence of SEQ ID NO: 2393, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 2739,

[0013] In certain embodiments, the first ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 2048, a CDR2 comprising an amino acid sequence of SEQ ID NO: 2394, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 2770.2 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO

[0014] In certain embodiments, the first ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 2123, a CDR2 comprising an amino acid sequence of SEQ ID NO: 2469, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 2815.

[0015] In certain embodiments, the first ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 2124, a CDR2 comprising an amino acid sequence of SEQ ID NO: 2470, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 2816.

[0016] In certain embodiments, the first ISVD comprises a CDRI comprising an amino acid sequence of SEQ ID NO: 2125, a CDR2 comprising an amino acid sequence of SEQ ID NO: 2471, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 2817.

[0017] In certain embodiments, the first ISVD comprises a CDRI comprising an amino acid sequence of SEQ ID NO: 6863, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6873, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 6883.

[0018] In certain embodiments, the first ISVD comprises a CDRI comprising an amino acid sequence of SEQ ID NO: 6864, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6874, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 6884.

[0019] In certain embodiments, the first ISVD comprises a CDRI comprising an amino acid sequence of SEQ ID NO: 6865, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6875, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 6885.

[0020] In certain embodiments, the first IS VD comprises a CDRI comprising an amino acid sequence of SEQ ID NO: 6866, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6876, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 6886.

[0021] In certain embodiments, the first ISVD comprises a CDRI comprising an amino acid sequence of SEQ ID NO: 6867, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6877, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 6887,

[0022] In certain embodiments, the second ISVD comprises a CDRI comprising an amino acid sequence of any one of SEQ ID NOs: 5209-5330 and 6976-6999, a CDR2 comprising an amino acid sequence of any one of SEQ ID NOs: 5453-5574 and 7024-7047, and a CDR3 comprising an amino acid sequence of any one of SEQ ID NOs: 5697-5818 and 7072-7095.

[0023] In certain embodiments, the second ISVD comprises a CDRI comprising an amino acid sequence of SEQ ID NO: 5225, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5469, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5713,

[0024] In certain embodiments, the second ISVD comprises a CDRI comprising an amino acid sequence of SEQ ID NO: 5256, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5500, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5744.3 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO

[0025] In certain embodiments, the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 5284, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5528, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5772, |0026] In certain embodiments, the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 5303, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5547, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5791.

[0027] In certain embodiments, the second ISVD comprises a CDRl comprising an amino acid sequence of SEQ ID NO: 5307, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5551, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5795.

[0028] In certain embodiments, the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7144, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7192, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7240.

[0029] In certain embodiments, the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7145, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7193, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7241.

[0030] In certain embodiments, the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7146, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7194, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7242,

[0031] In certain embodiments, the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7147, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7195, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7243.

[0032] In certain embodiments, the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7148, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7196, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7244,

[0033] In certain embodiments, the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7149, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7197, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7245.

[0034] In certain embodiments, the second ISVD comprises a CDRl comprising an amino acid sequence of SEQ ID NO: 7150, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7198, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7246.

[0035] In certain embodiments, the second ISVD comprises a CDRl comprising an amino acid sequence of SEQ ID NO: 7151, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7199, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7247.4 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO

[0036] In certain embodiments, the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7152, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7200, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7248, |0037] In certain embodiments, the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7153, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7201, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7249.

[0038] In certain embodiments, the second ISVD comprises a CDRI comprising an amino acid sequence of SEQ ID NO: 7154, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7202, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7250.

[0039] In certain embodiments, the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7155, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7203, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7251.

[0040] In certain embodiments, the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7156, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7204, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7252.

[0041] In certain embodiments, the second ISVD comprises a CDRI comprising an amino acid sequence of SEQ ID NO: 7157, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7205, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7253.

[0042] In certain embodiments, the second ISVD comprises a CDRI comprising an amino acid sequence of SEQ ID NO: 7158, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7206, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7254.

[0043] In certain embodiments, the second ISVD comprises a CDRI comprising an amino acid sequence of SEQ ID NO: 7159, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7207, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7255,

[0044] In certain embodiments, the second ISVD comprises a CDRI comprising an amino acid sequence of SEQ ID NO: 7160, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7208, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7256.

[0045] In certain embodiments, the second ISVD comprises a CDRI comprising an amino acid sequence of SEQ ID NO: 7161, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7209, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7257.

[0046] In certain embodiments, the second ISVD comprises a CDRI comprising an amino acid sequence of SEQ ID NO: 7162, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7210, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7258.5 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO

[0047] In certain embodiments, the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7163, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7211, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7259, |0048] In certain embodiments, the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7164, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7212, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7260.

[0049] In certain embodiments, the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7165, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7213, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7261.

[0050] In certain embodiments, the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7166, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7214, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7262.

[0051] In certain embodiments, the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7167, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7215, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7263.

[0052] In certain embodiments, the first ISVD comprises an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to any one of SEQ ID NOs: 10-182 and 6813-6817. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 85% (e.g,, at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to any one of SEQ ID NOs: 10-182 and 6813-6817. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to any one of SEQ ID NOs: 10-182 and 6813-6817. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or more) sequence identity to any one of SEQ ID NOs: 10-182 and 6813-6817. In certain embodiments, the first ISVD comprises an amino acid sequence of any one of SEQ ID NOs: 10-182 and 6813-6817. In certain embodiments, the first ISVD consists of an amino acid sequence of any one of SEQ ID NOs: 10-182 and 6813-6817.

[0053] In certain embodiments, the first ISVD comprises an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%. 83%, 84%, 85%. 86%, 87%, 88%. 89%, 90%, 91%.92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 71. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 6 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO85% (e.g, at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 71. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 71. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, ormore) sequence identity to SEQ ID NO: 71. In certain embodiments, the first ISVD comprises an amino acid sequence of SEQ ID NO: 71. In certain embodiments, the first ISVD consists of an amino acid sequence of SEQ ID NO: 71.

[0054] In certain embodiments, the first ISVD comprises an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, ormore) sequence identity to SEQ ID NO: 72. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 85% (e.g, at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%.98%, 99%, or more) sequence identity to SEQ ID NO: 72. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 72. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 95% (e.g, at least 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 72. In certain embodiments, the first ISVD comprises an amino acid sequence of SEQ ID NO: 72. In certain embodiments, the first ISVD consists of an amino acid sequence of SEQ ID NO: 72.

[0055] In certain embodiments, the first ISVD comprises an amino acid sequence having at least 80% (e.g, at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, ormore) sequence identity to SEQ ID NO: 73. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 85% (e.g, at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, ormore) sequence identity to SEQ ID NO: 73. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 73. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 95% (e.g, at least 95%, 96%, 97%, 98%, 99%, ormore) sequence identity to SEQ ID NO: 73. In certain embodiments, the first ISVD comprises an amino acid sequence of SEQ ID NO: 73.7 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOIn certain embodiments, the first ISVD consists of an amino acid sequence of SEQ ID NO: 73.

[0056] In certain embodiments, the first ISVD comprises an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 74. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 85% (e.g, at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%.98%, 99%, or more) sequence identity to SEQ ID NO: 74. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 74. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 95% (e.g, at least 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 74. In certain embodiments, the first ISVD comprises an amino acid sequence of SEQ ID NO: 74. In certain embodiments, the first ISVD consists of an amino acid sequence of SEQ ID NO: 74.

[0057] In certain embodiments, the first ISVD comprises an amino acid sequence having at least 80% (e.g, at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 149. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 149. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 149. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 149. In certain embodiments, the first ISVD comprises an amino acid sequence of SEQ ID NO: 149. In certain embodiments, the first ISVD consists of an amino acid sequence of SEQ ID NO: 149.

[0058] In certain embodiments, the first ISVD comprises an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity’ to SEQ ID NO: 150. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 150. In certain embodiments, the 8 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOfirst ISVD comprises an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 150. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 150. In certain embodiments, the first ISVD comprises an amino acid sequence of SEQ ID NO: 150. In certain embodiments, the first ISVD consists of an amino acid sequence of SEQ ID NO: 150.

[0059] In certain embodiments, the first ISVD comprises an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity’ to SEQ ID NO: 151. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 151. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 151. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 151. In certain embodiments, the first ISVD comprises an amino acid sequence of SEQ ID NO: 151. In certain embodiments, the first IS VD consists of an amino acid sequence of SEQ ID NO: 151.

[0060] In certain embodiments, the first ISVD comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6813. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6813. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6813. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6813, In certain embodiments, the first ISVD comprises an amino acid sequence of SEQ ID NO: 6813. In certain embodiments, the first ISVD consists of an amino acid sequence of SEQ ID NO: 6813.

[0061] In certain embodiments, the first ISVD comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6814. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6814. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6814. In certain embodiments, the first IS VD 9 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOcomprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6814. In certain embodiments, the first ISVD comprises an amino acid sequence of SEQ ID NO: 6814. In certain embodiments, the first ISVD consists of an amino acid sequence of SEQ ID NO: 6814.

[0062] In certain embodiments, the first IS VD comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6815. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6815. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6815. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6815. In certain embodiments, the first ISVD comprises an amino acid sequence of SEQ ID NO: 6815. In certain embodiments, the first ISVD consists of an amino acid sequence of SEQ ID NO: 6815.

[0063] In certain embodiments, the first ISVD comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6816. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6816. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6816. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6816, In certain embodiments, the first ISVD comprises an amino acid sequence of SEQ ID NO: 6816. In certain embodiments, the first ISVD consists of an amino acid sequence of SEQ ID NO: 6816.

[0064] In certain embodiments, the first ISVD comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6817. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6817. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6817. In certain embodiments, the first ISVD comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6817. In certain embodiments, the first ISVD comprises an amino acid sequence of SEQ ID NO: 6817. In certain embodiments, the first ISVD consists of an amino acid sequence of SEQ ID NO: 6817.

[0065] In certain embodiments, the second ISVD comprises an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to any one of 10 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOSEQ ID NOs: 356-477 and 6928-6951. In certain embodiments, the second ISVD comprises an amino acid sequence having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to any one of SEQ ID NOs: 356-477 and 6928-6951. In certain embodiments, the second ISVD comprises an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to any one of SEQ ID NOs: 356-477 and 6928-6951. In certain embodiments, the second ISVD comprises an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97?% 98%, 99%, or more) sequence identity to any one of SEQ ID NOs: 356-477 and 6928-6951. In certain embodiments, the second ISVD comprises an amino acid sequence of any one of SEQ ID NOs: 356-477 and 6928-6951. In certain embodiments, the second ISVD consists of an amino acid sequence of any one of SEQ ID NOs: 356-477 and 6928-6951.

[0066] In certain embodiments, the second ISVD comprises an amino acid sequence having at least 85?5> (e.g., at least 85%, 86%, 87%. 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 372. In certain embodiments, the second ISVD comprises an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 372. In certain embodiments, tire second ISVD comprises an amino acid sequence having at least 95% (e.g., at least 95?% 96%, 97%, 98%, 99%, or more) sequence identity’ to SEQ ID NO: 372. In certain embodiments, the second ISVD comprises an amino acid sequence of SEQ ID NO: 372. In certain embodiments, the second ISVD consists of an amino acid sequence of SEQ ID NO: 372.

[0067] In certain embodiments, the second ISVD comprises an amino acid sequence having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 403. In certain embodiments, the second ISVD comprises an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96?% 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 403. In certain embodiments, the second ISVD comprises an amino acid sequence having at least 95% (e.g., at least 95%, 96?% 97%, 98%, 99?% or more) sequence identity’ to SEQ ID NO: 403. In certain embodiments, the second ISVD comprises an amino acid sequence of SEQ ID NO: 403. In certain embodiments, the second ISVD consists of an amino acid sequence of SEQ ID NO: 403

[0068] In certain embodiments, the second ISVD comprises an amino acid sequence having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92?% 93%, 94%, 95?%11 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 431. In certain embodiments, the second ISVD comprises an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 431. In certain embodiments, the second ISVD comprises an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 431. In certain embodiments, the second ISVD comprises an amino acid sequence of SEQ ID NO: 431. In certain embodiments, the second ISVD consists of an amino acid sequence of SEQ ID NO: 431.

[0069] In certain embodiments, the second ISVD comprises an amino acid sequence having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 450. In certain embodiments, the second ISVD comprises an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 450. In certain embodiments, the second ISVD comprises an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 450. In certain embodiments, the second ISVD comprises an amino acid sequence of SEQ ID NO: 450. In certain embodiments, the second ISVD consists of an amino acid sequence of SEQ ID NO: 450.

[0070] In certain embodiments, the second ISVD comprises an amino acid sequence having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 454. In certain embodiments, the second ISVD comprises an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 454. In certain embodiments, the second ISVD comprises an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 454. In certain embodiments, the second ISVD comprises an amino acid sequence of SEQ ID NO: 454. In certain embodiments, the second ISVD consists of an amino acid sequence of SEQ ID NO: 454.

[0071] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6928. In certain embodiments, the bi specific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6928. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO:12 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO6928. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6928. In certain embodiments, tire bispecific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6928. In certain embodiments, the bispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6928.

[0072] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6929. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6929. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6929, In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6929. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6929. In certain embodiments, the bispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6929.

[0073] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6930. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6930. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6930. In certain embodiments, tire bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6930, In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6930. In certain embodiments, the bispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6930.

[0074] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6931. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO:13 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO6931. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6931. In certain embodiments, tire bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6931. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6931. In certain embodiments, the bispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6931.

[0075] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6932. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6932, In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6932. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6932. In certain embodiments, the bi specific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6932. In certain embodiments, the bispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6932.

[0076] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6933. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6933. In certain embodiments, tire bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6933, In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6933. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6933. In certain embodiments, the bispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6933.

[0077] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO:14 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO6934. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6934. In certain embodiments, tire bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6934. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6934. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6934. in certain embodiments, the bispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6934.

[0078] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6935, In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6935. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6935. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6935. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6935. In certain embodiments, the bispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6935.

[0079] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6936. In certain embodiments, tire bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6936, In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6936. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6936. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6936. In certain embodiments, the bispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6936.15 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO

[0080] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6937. In certain embodiments, tire bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6937. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6937. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6937. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6937, In certain embodiments, the bispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6937.

[0081] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6938. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6938. In certain embodiments, the bi specific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6938. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6938. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6938. In certain embodiments, the bispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6938.

[0082] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6939, In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6939. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6939. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6939. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6939. In certain embodiments, the 16 / 647IPTS / 200261047.5Attorney Docket: AVT-001WObispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6939.

[0083] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6940. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6940. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6940. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6940. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6940. In certain embodiments, the bispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6940.

[0084] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6941. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6941. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6941. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95 % sequence identity to SEQ ID NO: 6941. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6941, In certain embodiments, the bispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6941.

[0085] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6942. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6942. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6942. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO:17 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO6942. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6942. In certain embodiments, the bispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6942.

[0086] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6943. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6943. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6943. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6943, In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6943. In certain embodiments, the bispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6943.

[0087] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6944. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6944. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6944. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6944. In certain embodiments, tire bispecific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6944. In certain embodiments, the bispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6944.

[0088] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6945. In certain embodiments, the bi specific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6945. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO:18 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO6945. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6945. In certain embodiments, tire bispecific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6945. In certain embodiments, the bispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6945.

[0089] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6946. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6946. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6946, In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6946. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6946. In certain embodiments, the bispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6946.

[0090] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6947. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6947. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6947. In certain embodiments, tire bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6947, In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6947. In certain embodiments, the bispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6947.

[0091] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6948. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO:19 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO6948. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6948. In certain embodiments, tire bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6948. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6948. In certain embodiments, the bispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6948.

[0092] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6949. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6949, In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6949. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6949. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6949. In certain embodiments, the bispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6949.

[0093] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6950. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6950. In certain embodiments, tire bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6950, In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6950. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6950. In certain embodiments, the bispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6950.

[0094] In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO:20 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO6951. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 6951. In certain embodiments, tire bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6951. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 6951. In certain embodiments, the bispecific polypeptide comprises a second ISVD comprising an amino acid sequence of SEQ ID NO: 6951. In certain embodiments, the bispecific polypeptide comprises a second ISVD consisting of an amino acid sequence of SEQ ID NO: 6951.|0095] In certain embodiments, the bispecific polypeptide comprises a first ISVD comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NO: 6813, and a second ISVD comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NO: 6928.

[0096] In certain embodiments, the bispecific polypeptide comprises a first ISVD comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NO: 6813, and a second ISVD comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity’ to SEQ ID NO: 6929,

[0097] In certain embodiments, the bispecific polypeptide comprises a first ISVD comprising an amino acid sequence having at least 80%, 85%, 90%, 95 %, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NO: 6813, and a second ISVD comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NO: 6931.

[0098] In certain embodiments, the bispecific polypeptide comprises a first ISVD comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NO: 6813, and a second ISVD comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity’ to SEQ ID NO: 6932.

[0099] In certain embodiments, the bispecific polypeptide comprises a first ISVD comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NO: 6817, and a second ISVD comprising an amino acid21 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOsequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NO: 6928.

[0100] In certain embodiments, the bispecific polypeptide comprises a first ISVD comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NO: 6817, and a second ISVD comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NO: 6929.

[0101] In certain embodiments, the bispecific polypeptide comprises a first ISVD comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity’ to SEQ ID NO: 6817, and a second ISVD comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NO: 6931.

[0102] In certain embodiments, the bispecific polypeptide comprises a first ISVD comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NO: 6817, and a second ISVD comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NO: 6932.

[0103] In certain embodiments, the first ISVD and the second ISVD are connected by a peptide linker. In certain embodiments, the peptide linker comprises an amino acid sequence having at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to the amino acid sequence of any one of SEQ ID NOs: 6795-6804. In certain embodiments, the peptide linker comprises an amino acid sequence of any one of SEQ ID NOs: 6795-6804. In certain embodiments, tire peptide linker consists of an amino acid sequence of any one of SEQ ID NOs: 6795-6804. In certain embodiments, the peptide linker comprises an amino acid sequence having at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%;.. 98%, 99%, or more sequence identity to the amino acid sequence of SEQ ID NO: 6795, In certain embodiments, the peptide linker comprises an amino acid sequence of SEQ ID NO: 6795. In certain embodiments, the peptide linker consists of an amino acid sequence of SEQ ID NO: 6795. In certain embodiments, the peptide linker comprises an amino acid sequence having at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to the amino acid sequence of SEQ ID NO: 6796. In certain embodiments, the peptide linker comprises an amino acid sequence of SEQ ID NO: 6796. In certain embodiments, the peptide linker consists of an amino acid sequence of SEQ ID NO: 6796. In certain embodiments, the peptide linker comprises an 22 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOamino acid sequence having at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to the amino acid sequence of SEQ ID NO: 6797. In certain embodiments, the peptide linker comprises an amino acid sequence of SEQ ID NO: 6797. In certain embodiments, the peptide linker consists of an amino acid sequence of SEQ ID NO: 6797. In certain embodiments, the peptide linker comprises an amino acid sequence having at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to the amino acid sequence of SEQ ID NO: 6798. In certain embodiments, the peptide linker comprises an amino acid sequence of SEQ ID NO: 6798. In certain embodiments, the peptide linker consists of an amino acid sequence of SEQ ID NO: 6798. In certain embodiments, the peptide linker consists of an amino acid sequence of SEQ ID NO: 6799. In certain embodiments, the peptide linker consists of an amino acid sequence of SEQ ID NO: 6800. In certain embodiments, the peptide linker consists of an amino acid sequence of SEQ ID NO: 6801. In certain embodiments, the peptide linker consists of an amino acid sequence of SEQ ID NO: 6802. In certain embodiments, tire peptide linker consists of an amino acid sequence of SEQ ID NO: 6803. In certain embodiments, the peptide linker consists of an amino acid sequence of SEQ ID NO: 6804.

[0104] In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 7456. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 7456. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 7456. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 7456. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7456. In certain embodiments, tire bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7456. In certain embodiments, the bispecific polypeptide consists of an amino acid sequence of SEQ ID NO: 7456.

[0105] In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 7457. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 7457. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 7457. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 7457. In certain23 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOembodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7457. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7457. In certain embodiments, the bispecific polypeptide consists of an amino acid sequence of SEQ ID NO: 7457.

[0106] In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 7458. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 7458. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 7458. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 7458. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7458. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7458. In certain embodiments, the bispecific polypeptide consists of an amino acid sequence of SEQ ID NO: 7458.

[0107] In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 7459. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 7459. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 7459. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 7459. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7459. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7459. In certain embodiments, the bispecific polypeptide consists of an amino acid sequence of SEQ ID NO: 7459.

[0108] In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 7460. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 7460. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 7460. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 7460. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO:24 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO7460. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7460. In certain embodiments, the bispecific polypeptide consists of an amino acid sequence of SEQ ID NO: 7460.|0109] In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 7461. In certain embodiments, the bispecific polypeptide composes an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 7461. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 7461. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 7461. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7461. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7461. In certain embodiments, the bispecific polypeptide consists of an amino acid sequence of SEQ ID NO: 7461.

[0110] In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 7462. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 7462. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 7462, In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 7462. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7462. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7462, In certain embodiments, the bispecific polypeptide consists of an amino acid sequence of SEQ ID NO: 7462.

[0111] In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 7463. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 7463. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 7463. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 7463. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7463. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence 25 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOof SEQ ID NO: 7463. In certain embodiments, the bispecific polypeptide consists of an amino acid sequence of SEQ ID NO: 7463.

[0112] In certain embodiments, tire bispecific polypeptide comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 7464. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 7464. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 7464. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 7464. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7464. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7464. In certain embodiments, tire bispecific polypeptide consists of an amino acid sequence of SEQ ID NO: 7464.

[0113] In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 7465. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 7465. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 7465. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 7465. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7465. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7465. In certain embodiments, the bispecific polypeptide consists of an amino acid sequence of SEQ ID NO: 7465,

[0114] In certain embodiments, tire bispecific polypeptide comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 7466. In certain embodiments, the bispecific polypeptide composes an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 7466. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 7466. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 7466. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7466. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence26 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOof SEQ ID NO: 7466. In certain embodiments, the bispecific polypeptide consists of an amino acid sequence of SEQ ID NO: 7466.

[0115] In certain embodiments, tire bispecific polypeptide comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 7467. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 7467. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 7467. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 7467. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7467. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7467. In certain embodiments, tire bispecific polypeptide consists of an amino acid sequence of SEQ ID NO: 7467.

[0116] In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 7468. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 7468. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 7468. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 7468. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7468. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7468. In certain embodiments, the bispecific polypeptide consists of an amino acid sequence of SEQ ID NO: 7468,

[0117] In certain embodiments, tire bispecific polypeptide comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 7469. In certain embodiments, the bispecific polypeptide composes an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 7469. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 7469. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 7469. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7469. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence27 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOof SEQ ID NO: 7469. In certain embodiments, the bispecific polypeptide consists of an amino acid sequence of SEQ ID NO: 7469.

[0118] In certain embodiments, tire bispecific polypeptide comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 7470. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 7470. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 7470. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 7470. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7470. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7470. In certain embodiments, tire bispecific polypeptide consists of an amino acid sequence of SEQ ID NO: 7470.

[0119] In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 7471. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 7471. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 7471. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 7471. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7471. In certain embodiments, the bispecific polypeptide comprises an amino acid sequence of SEQ ID NO: 7471. In certain embodiments, the bispecific polypeptide consists of an amino acid sequence of SEQ ID NO: 7471,

[0120] In certain embodiments, the first ISVD specifically binds to IL- 1(3 with a dissociation rate (koft) between l. OxlO’V and 2.2 - ICb ’ (e.g., l. OxlO’,. xlO'Y1, 9.8xl0-2s’!, 9.7xI0‘2s’],. xlO', 9.5xl0~2s“’, AxlO’, 9.3xl0"2s’', 9.2xl0-2s’1, 9.1xl0"2s’', 9.0x10’ V, s.oxiO’V, s.sxio’V, s^xiO’V, s.exiO’V, s.sxicrV, SNxiO’V, s.sxicrV,S^xlO’V, S.lxlO’V, S. OxlO’V, 7.9xl0’2s’1, 7.8xl0’2s’1, 7.7xl0’2s’1, 7.6xl0’2s’1, 7.5x10’2s’’, 7.4xl0’2s’1, 7.3xl0’2s’1, 7.2 lO-'s’l 7.1xl0’2s’i, 7.0xl0’2s’!, ONxlO’, 6.8xl0’2s’!, 6.7x10’, 6.6 fir ’s '.. SxlO’, 6.4xl0’2s’!, 6.3x]0’2s’1, 6.2xl0"2s’', 6.1 x]0’2s’1, 6.0x10"2s-1, 5.9xio-2s’’, 5.8x10V, sjxio-1, sfixicr, s. SxioV, 5.4> ocr, sjxio’, S^xlO’V, S.lxlO’V, S. OxlO’, 4.9xl0’2s’1, 4.8xl0’2s’1, 4.7xl0’2s’1, 4.6xl0"2s’1, 4.5 fir2s"1, 4.4xl0’2s’’, 4.3xl0’2s’1, 4.2xl0’2s’i, 4.1xl0’2s"‘, 4.0xl0"2s’i, 3.9xl0’2s"‘, S.gxlO’,28 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO3.7x l0-2s- 3.6X 10-2S'!, 3.5X 10-1, 3.4xl0’2s’], 3.3x l0’2s’1, 3.2x l0’2s’’, 3.1x l0’2s’1, 3.0x 10’2s’1, 2.9x l0’2s’1, 2.8X 10’2S’1, 2.7! 0"' '!. 2.6x l0“2s’i, 2.5> h'r'S'!. 2.4x l0“2s’i, 2.3xl0’2s’\ 2.2x I0’2s’1, 2.1 x l0’2s’\ 2.0x 10’2s’\ l. xlO’1, l. Sx O’, IJx lO’, l. x lO’, 1.5x 10’2s'1, l^x lO’, IJx lO’1, l^x lO’, l.l x lO’, l. Ox lO’, 9.9x l0’3s’I;9.8xl0’3s’1, 9.7x l0’3s’], 9.6x l0’3s’1, 9.5x l0’3s’], 9.4xl0’3s’1, 9.3x l0’3s’’, 9.2x l0’3s’1, 9.1 x l0’3s’’, 9.0x 10’3s’1, S. x lO’, 8.8x ] 0’3s’1, 8.7x l0"3s’i, 8.6x l0’3s"!, S. x lO’, 8.4x J 0’3s"\ S. Sx lO’, 8.2x l0’3s’\ 8.1 x I0’3s’\ 8.0 Hr 's4. 7.9x I0’3s’1, 7.8x l0’3s'1, 7.7x ] 0’3s’1, 7.6x10V, 7.5x 10’3s’1, 7.4x l0’3s’1, 7.3x l0’3s’1, 7.2x l0’3s’i, 7.1 x l0’3s’1, 7.0x l0’3s’i, ^x lO’, 6.8x l0’3s’\ 6.7X 10’3S’\ 6.6X 10’3S’], 6.5X 10’3S’\ 6.4X 10’3S’], 6.3X 10’3S’1, 6.2X 10’3S’’, 6.1 X 10’3S’1, 6.0x 10’3s'1,. Ox l O’V, S. SxlO’, S x lO’V, S. x lO’, S. Sx J O’, S^x lO’, 5.3 X ] 0’3S"\ 5.2X I0’3S’\ 5.1 l O. 5.0X I0’3S’\ 4.9X 10’3S’1, 4.8X ] 0’3S’1, 4.7X 10’3S'1, 4.6X ] 0’3S’1, 4.5 Hr3s"1, 4.4x l0’3s’’, 4.3X 10’3S’1, 4.2X 10’3S’1, 4.1 X 10’3S’1, 4.0x l0’3s’i, 3.9X 10’3S’!, S. Sx lO’, 3.7 Hr's1. 3,6 Hi'V. 3.5 Hr. SAx lO’, 3.3x l0’3s’', 3.2x ]0’3s’1, 3.1 x l0"3s’', 3.0x 10’3s’1, 2.9x l0"3s'1, 2.8X ] O’, 2.7X 10V, 2.6X 10’3S’1, 2.5x l0’3s’i, 2.4x l0’3s’1, 2.3xl0’3s’i, 2.2x l0’3s’1, 2.1 x l0’3s’1, 2.0x l0’3s’1, l. xlO’, l. Sx lO’1, IJx lO’, l. x lO’1, 1.5x 10’3s’’, 1.4x l0’3s’1, 1.3X 10’3S’’, 1.2x l0’3s’!, l.l x lO’, l. Ox lO’1, 9.9x l0’4s’1, 9.8x l0’4s’!, 9.7x 10’4S’\ 9.6X 10’4S’!, Jx lO’, 9.4X 10’4S’!, 9.3X 10’4S’1, ^x lO’, 9,] x l0’4s’1, 9.0x 10’4s’1, 8.9X 10’4S’\ S. SxlO’V, SJx lO’V, S. x lO’, S. Sx lO’V, 8.4 Hr. SJxlO’V, 8.2X 10’4S’!, S.lx lO’, 8.0x l0’4s’], 7.9xl0’4s’1, 7.8x l0’4s’’, 7.7x l0’4s’1, 7.6x l0’4s’’, 7.5x 10’4s’\ 7.4x l0’4s’1, 7.3x l 0’4s’1, 7.2x l0"4s’i, 7.1 x lO’, 7.0x l0’4s’i, 6.9x ] 0’4s"\. SxlO’, ejx lO’, 6.6x l0’4s’\ e. Sx lO’, 6.4xl0’4s’\ Jx lO’, 6.2x l0’4s’\.lx lO’, 6.0x 10’, S. Ox lO’, 5.8X 10-, 5.7 Kr' ’ S.ex IO’1, S. Sx lO’, S^x lO’, SJxlO’, 5.2X 10’4S’\.1 X 10’4S’!, 5.0X 10’4S’\ 4.9X 10’4S’!, 4.8x l0’4s’1, 4.7> < 10’4s’], 4.6 Hr's'1. 4.5x 10’, 4.4x l 0’4s’\ 4.3 i - 's'1. 4.2X 10’4S"!, 4, l x l0’4s’i, 4.0x l0’4s"!, S. x lO’, 3.8x l0’4s"\ 3.7x l0’4s’\ S. x lO’, 3.5x l0’4s’\ S^xlO’, 3.3x l0’4s’\ SJx lO’V, 3.1 x l0’4s’\ 3.0x 10’4s’1, 2.9X 10’4S’’, 2.8X 10’4S’1, 2.7X 10’4S’1, 2.6X 10’4S’!, 2.5 X 10’4S’’, 2.4X 10’4S’1, 2.3 X 10’4S’’, and 2.2x 10‘4S’]).

[0121] In certain embodiments, the second ISVD specifically binds to Col2 with a koff between l^xlO’V and O.lx lO’V (e.g., l^x lO’V, l.lx lO’V1, l. Ox lO’V, O. Ox lO’V, 9.8x l0’4s’1, 9.7X 10’4S’!, 9.6X 10’4S’1, 9.5X 10’4S’], 9.4X 10’4S’1, 9.3X 10’4S’’, 9.2X 10’4, 9.1 X 10’4S’!,. Ox lO’V, 8.9X 10’4S’!, S. Sx lO’, 8.7X 10’4S’!, 8.6X 10’4S’1, 8.5 X 10"4S’', 8.4X 10’4S’1, 8.3X 10’4s-1, 8.2x l 0’4, S.l x lO’, S. Ox lO’V, 7.9X 10’4S’1, 7.8X 10’4S’1, 7.7X 10’4S’1, 7.6X 10’4S’1, 7.5 X 10'4s’1, 7.4x l0’4s’1, 7.3x l0’4s’1, 7.2x l0’4s’1, 7.1 x l0’4s’i, 7.0x l0’4s’1, ^x lO’, O. SxlO’V, 6.7x l0’4s’], e. x lO’, 6.5x l0’4s’], e.dxlO’, 6.3x l0’4s’], 6.2x l0’4s’1, 6.1 x l0’4s’], 6.0x 10’29 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO4s"’, 5.9xlO, 5.8X 10V1, 5.7 lV. 5.6x10V, 5.5xl0V, 5.4x10V, 5.3x10V, 5.2x10, 5.1x10V1, 5.0x10, 4.9x10, 4.8x10, 4.7 DOV, 4.6x10V1, 4.5x10", 4.4x10V1, 4.3x10V1, 4.2x10V1, 4.1x10V1, 4.0x10V1, 3.9x10V1, 3.8x10V1, 3.7x10V1, 3.6x10V, 3.5x10V1, 3.4x10, 3.3x10V1, 3.2x10V1, 3.1x10V1, 3.0x10", 2.9x10V1, 2.8x10V1, 2.7x10V, 2.6x10V1, 2.5x10V1, 2.4x10V1, 2.3x10V1, 2.2x10V, 2. IxiOV, 2.0x10V, 1.9x10V1, 1.8x10V, 1.7x10V1, 1.6x10V1, 1.5x10", 1.4x10V1, 1.3x10V1, 1.2x10V1, 1.1 x10V, 1.0x10V1, 9.9x10V1, 9.8x10V1, 9.7x10, 9.6x10V1, 9.5x101, 9.4x10V1, 9.3x10, 9.2x10V1, and 9.1x10 ) in a bivalent format (i.e., a construct comprising two anti-Co!2 ISVDs).

[0122] In certain embodiments, the first ISVD specifically binds to IL- 1 P with a dissociation constant (KD) ofbetween 1.1 xlO"7M and 2.4xlO"10M (e.g., 1.1 xlO"7, l. OxlO"7, 9.9xl0"8, 9.8xl0"s, 9.7xl0"s, 9.6xl0"8, 9.5 x IO"8, 9.4xl0"8, 9.3 x IO"8, 9.2xl0"8, 9. LIO"8, 9.0xl0"8, 8.9xl0"8, 8.8xl0"s, 8.7xl0"8, 8.6xl0"8, SVW"8, 8.4xl0"8, 8.3xl0"8, 8.2xl0"8, 8.1> <10"8, 8.0xl0"8, 7.9xl0"8, 7.8xl0"8, 7.7xl0"8, 7.6xl0"8, 7.5xl0"8, 7.4xl0"8, 7.3xl0"8, 7.2xl0"8, 7. lx IO"8, 7. Ox IO"8, 6.9xl0"8, 6.8xl0"8, 6.7xl0"8, 6.6xl0"8, 6.5 x IO"8, 6.4xl0"8, 6.3 x IO"8, 6.2. X10"8, 6.1X10"8, 6.0 - IO"8, 5.9xl0"8, 5.8xl0"8, 5.7xl0"8, 5.6xl0"8, 5.5xl0"8, 5.4xl0"8, 5 3 IO'8. 5.2xl0"8, 5.1 xlO"8, 5.0xl0"8, 4.9xl0"8, 4.8xl0"8, 4.7xl0"8, 4.6xl0"8, 4.5xl0“8, 4.4xl0"8, 4.3xl0"8, 4.2xl0"8, 4.1xl0"8, 4.0xl0"8, 3.9xl0"8, 3.8xl0"8, 3.7xl0"8, 3.6xl0"8, 3.5xl0"8, 3.4xl0"8, 3.3xl0"8, 3.2xl0"8, 3. LIO"8, 3.0xl0"8, 2.9> IO"8, 2.8xl0"8, 2.7xl0"8, 2.6xl0"8, 2.5xl0"8, 2.4xl0"8, 2.3xl0"8, 2.2xl0"8, 2.1 xl0"8, 2.0xl0"8, 1.9xl0"8, IVIO"8, 1.7xl0"8, 1.6xl0"8, 1.5xl0"8, 1.4xl0"8, 1.3xl0"8, iW, l.l xlO"8, l. OxlO"8, 9.0xl0"9, 8.9xl0"9, 8.8xl0"9, 8.7 hr9. 8.6xl0"9, 8.5xl0"9, 8.4xl0"9, 8.3xl0"9, 8.2xl0"9, 8.1xl0"9, 8.0xl0"9, 7.9xl0"9, 7.8 hr9. 7.7 hr". 7.6xl0"9, 7.5xl0"9, 7.4xl0"9, 7.3xl0"9, 7.2. X10"9, 7 I IO'9. 7.0xl0"9, 6.9xl0"9, 6.8xl0"9, 6.7xl0"9, 6.6xl0"9, 6.5xl0"9, 6.4xl0"9, 6.3xl0’9, 6.2 IO'9. 6.1 X10"9, 6.0xl0"9, 5.9xl0"9, 5.8xl0"9, 5.7xl0"9, 5.6xl0"9, 5.5xl0"9, 5.4xl0“9, 5.3xl0"9, 5.2xl0"9, 5.1xl0"9, 5.0xl0"9, 4.9xl0-9, 4.8xl0"9, 4.7xl0"9, 4.6X 10"9, 4.5xl0"9, 4.4xl0"9, 4.3 r9. 4.2xl0"9, 4.1xl0"9, 4 0 K)'. 3 VIO"9, 3.8xl0"9, 3.7xl0"9, 3.6xl0"9, 3.5xl0"9, 3.4xl0"9, 3.3xl0"9, 3.2xl0"9, 3. LIO"9, 3.0xl0"9, 2.9xl0"9, 2.8xl0"9, 2.7xl0"9, 2.6x0"9, 2.5xl0"9, 2.4xl0"9, 2.3xl0"9, 2.2xl0"9, 2.1xl0"9, 2.0xl0"9, 1.9xl0"9, 1.8xl0"9, 1.7xl0"9, 1.6xl0"9, 1.5xl0"9, 1.4xl0"9, 1.3xl0"9, 1.2xl0"9, l.lxlO"9, l. OxlO"9, 9.9xlO"10, 9.8xlO"10, 9.7xlO’10, 9.6X1O"10, 9.5X1O’10, 9.4xlO"10, 9.3xlO"10, 9.2xlO"10, 9.1 xlO"10, 9. OxlO"10, 8.9xlO"10, 8.8xlO“10, 8.7xlO"10, 8.6xlO"10, 8.5xlO"10, 8.4xlO"10, 8.3xlO"10, 8.2xlO"10, SVIO"10, S. OxlO"10, 7.9xlO"10, 7.8xlO"10, 7.7xlO"10, 7.6xlO"10, 7.5xlO"10, 7.4xlO"10, 7.3xlO"10, 7.2xlO"10, 7. LIO"10, 7. OxlO"10, 6.9xlO"10, 6.8xlO"10, 6.7xlO"10, 6.6xlO"10, 6.5xlO"10, 6.4xlO"10, 6.3xl0"!°, 6.2xlO"10,30 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO6.1 x IO’10, 6.0x 10-’°, 5.9X 1O’10, 5.8x 10-’°, 5.7X 1O’’0, 5.6X 1O’’0, 5.5x W10, 5.4x lO'10, 5.3x lO'10,.2x 10-’°, 5.1 x 10-’°, 5.0x 10-'°, 4.9x 10-'°, 4.8x 10-’°, 4.7x 10-'°, 4.6x 10-’°, 4.5 > AO’10, 4.4x l0’i0, 4.3 x 10-’°, 4.2x 10-’°, 4.1 x 10-’°, 4.0x 10-’°, 3.9x 10-’°, 3.8x 10-’°, 3.7x ] 0-’°, 3.6X 1 O’’0, 3.5 X 1 O’’0, 3.4x 10-’°, 3.3 x 10-’°, 3.2x 10-’°, 3.1 x 10-’°, 3.0x 10-’°, 2.9x 10-’°, 2.8x 10-’°, 2.7x 10-’°, 2.6x 10'’°, 2.5 x IO'10, and 2.4x IO"’0M), as measured by surface plasmon resonance (SPR).

[0123] In certain embodiments, the second ISVD specifically binds to Col2 with a KD of between 4.0x 10’° M and 1.8x l0’9M (e.g., 4.0x l 0'6, 3.9x 10’°, 3.8x 10-°, 3.7x 10'°, 3.6x l0'6, 3.5 x 10'°, 3.4x l0-6, 3.3hr9. 3.2x l0’6, 3. 1 / H r6. 3.0x 10-°, 2.9x 10'°, 2.8x 10-°, 2.7x 10'°, 2.6 x 10’°, 2.5 x 10’°, 2.4 < 10'°, 2.3 / 10‘°, 2.2 x IO’6, 2.1 x 1 O’6, 2.0 x 10'°, 1.9 x 10'°, 1.8 x 10'°, 1.7x 10’°, 1.6x l 0-6, 1.5x 10-°, 1.4x 10’°, 1.3 x 10'°, 1.2x 10'°, 1.1 x 10'°, 1.0x 10’°, 9.0x l0’7, 8.9 / 10-7, 8.8 / 10-7, 8.7x l0'7, 8.6 / 10-7, 8.5 X 10'7, 8.4 1 O'7. 8.3 / 10'7, 8.2x l0'7, 8.1 x l0’7, 8.0 / 10-7, 7.9x l0'7, 7.8X 10’7, 7.7x l0'7, 7.6X 10'7, 7. X 10'7, 7.4 hr". 7.3 / 10-7, 7.2 / 10-7, 7.1 X 10'7, 7.0X 10’7, 6.9x l0’7, 6.8x l0"7, 6.7 / 10-7, 6 6 i rf. 6. x l0’7, 6.4x l0’7, 6.3 x l0'7, 6.2 / 10'7, 6.1 / 10'7, 6.0x l0’7, 5.9x lCr7, 5.8X 10'7, 5.7X 10'7, 5.6x l0’7, 5.5 x l0’7, 5.4 / 10'7, 5.3 X 10'7, 5.2X 10’7, 5.1 X 10'7, 5.0x l0'7, 4.9x l0-7, 4.8x l0-7, 4.7x l0'7, 4.6X 10'7, 4.5 / 10'7, 4.4 / 10'7, 4.3 X 10'7, or 4.2 / 10-7M, 4. l x IO'7, 4.0x IO'7, 3.9 hr". 3.8 / 10-7, 3.7x l0'7, 3.6x l0'7, 3.5x l0’7, 3.4 / 10-7, 3.3 x l0’7, 3.2x l0’7, 5. 1 10 ". 3.0 / 10-7, 2.9 / 10'7, 2.8x l0'7, 2.7x l0’7, 2.6 x 1 O’7, 2.5 x 1 O'7, 2.4 x 1 O'7, 2.3 x 1 O’7. 2.2 x 1 O’7, 2. 1 x 1 O’7, 2.0 x 1 O'7, 1.9 x 1 O'7, 1.8 x 1 O’7, 1.7 / 10-7, 1.6x l0'7, 1.5X 10’7, 1.4x l0’7, 1.3 X 10'7, I Jx lO'7, l. l x lO'7, l. Ox lO'7, 9.0X 10'8, 8.9x l0's, 8.8x lO-s, 8.7x l0'8, 8.6x l0’8, 8.5x lO’8, 8.4 / 10'8, 8.3 x lO’8, 8.2x l 0’8, 8. 1 Ix.8.0x l0‘8, 7.9X 10'8, 7.8x lCr8, 7.7 / 10'8, 7.6X 10'8, 7.5 x l 0'8, 7.4x l0’8, 7.3 x l0’8, 7.2 / 10'8, 7. l x IO'8, 7. Ox IO'8, 6.9 / 10-8, 6.8 / IO’8, 6.7 / 1Q-8, 6.6 / 10-8, 6.5 x IO'8, 6.4 / 10-8, 6.3 / IO'8, 6.2. X 10'8, 6.1 X 10'8, 6.0 - 10‘8,.9 / 10-8,.8x W8, 5.7x l0'8, 5.6x W8, 5.5x lO’8, 5.4 / 10'8, 5.3 x l O'8, 5.2 / 10-8, 5.1 X 10'8, 5.0 / 10-8, 4.9x l0-8, 4.8x l0-s, 4.7x l0-8, 4.6 / 10'8, 4.5 / 10'8, 4.4 / 10'8, 4.3 X 10'8, or 4.2x l0‘8M, 4.1 X 10'8, 4.0x l 0’8, 3.9x l0’8, 3.8x l0‘8, 3.7x l0'8, 3.6 / 10'8, 3.5 / 10-8, 3.4x l0'8, 3.3 x l0’8, 3.2x l0'8, 3.1 / 10'8, 3.0x l0'8, 2.9> 10‘8, 2.8 / 10-8, 2.7 / 1Q-8, 2.6x l0'8, 2.5 / 10-8, 2.4 / 10'8, 2.3 x l0'8, 2.2x l0-8, 2.1 x l 0-8, 2.0x l0’8, 1.9x l0’8, 1.8x l0'8, 1.7x l0'8, 1.6X 10'8, 1.5x lO’8, 1.4 / 10’8, 1.3X 10’8, I.2X 10'8, l. l x lO’8, l. Ox lO’8, 9.0 / 10'9, 8.9x l0'9, 8.8X 10'9, 8.7 hr9. 8.6 / 10’9, 8.5 / 1Q-9, 8.4 / 10-9, 8.3 / 10'9, 8.2X 10'9, 8.1 x l0'9, 8.0 / 10'9, 7.9x l0’9, 7.8 hr9. 7.7> dO’9, 7.6 / 10'9, 7.5 x l0'9, 7.4x W9, 7.3 x l0'9, 7.2x l0’9, 7.1 X 10'9, 7.0 / 10-9, 6.9X 10'9, 6.8x W9, 6.7 / 1Q-9, 6.6 / 10-9, 6.5 / 10'9, 6.4 / 10'9, 6.3x l0’9, 6.2x l 0'9, 6.1 X 10'9, 6.0x l0’9, 5.9 / 10’9, 5.8 / 10'9, 5.7 / 10'9, 5.6 / 10'9, 5.5 / lCr9, 5.4 / 10'9, 5.3 X 10’9, 5.2 / 10'9, 5.1 X 10'9, 5.0 / 10-9, 4.9x l0-9, 4.8x l0-9, 4.7x l0'9, 4.6 / 10'9, 4.5 x l0’9, 4.4X 10'9, 4.3 / 10'9, or 4.2x l0'9, 4.1 X 10'9, 4.0x l0'9, 3.9* 10-9, 3.8 | (9. 3.7 / 1Q-9, 3.6x l0'9,31 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO3.5xl0'9, 3.4xl0'9, 3.3' lO-9, 3.2 / 10'9, 3.1 / 10’9, 3.0 / 10’9, 2.9 / 10’9, 2.8 / 10’9, 2.7xl0'9, 2.6 / i O'9. 2.5xl0'9, 2.4xl0’9, 2.3 / 10’9, 2.2 / 10’9, 2.1 / 10~9, 2.0 / I0"9, 1.9 / I0"9, and 1.8 / 10"9M) in a bivalent format ( / .<?., a construct comprising two anti-Co!2 ISVDs), as measured b\ SPR. in certain embodiments, the second ISVD specifically binds to Col2 with a KD of between 6.0X10’8and 1.8xlO’9M (e.g, 6.0 / 10'8, 5.9> 10'8, 5.8X10'8, 5.7 / W8, 5.6 / 10‘8, 5.5xl0’8, 5.4xl0‘8, 5.3xl0’s, 5.2xl0’8, 5.1xl0"8, 5.0 / 10’8, 4.9zl0’8, 4.8xl0'8, 4.7 / 10’8, 4.6xl0‘8, 4.5xl0‘8, 4.4X10'8, 4.3xicr8, 4.2 / 10"8, 4.1 / 10’8, 4.0 / 10'8, 3.9 / 10’8, 3.8 / 10’8, 3.7 / 10‘8, 3.6xl0'8, 3.5xl0'8, 3.4> IO'8, 3.3 / IO'8, 3.2x 10'8, 3. LIO'8, 3.0 / IO'8, 2.9 / Hr8. 2.8 / 10'8, 2.7xl0'8, 2.6 / 10'8, 2.5xl0'8, 2.4 / 10-8, 2.3xl0-8, 2.2xl0‘8, 2.1xl0-8, 2.0 / I0’8, 1.9 / 10'8, 1.8zl0’8, 1.7 / 10'8, 1.6X10’8, 1.5xl0’8, 1.4 / 10'8, 1.3 / 10'8, 1.2 / I0"8, l.lxlO’8, I.0 / 10'8, 9.0 / 10’9, 8.9 / 0'9, 8.8 / 10'9, 8.7 1 O’9. 8.6 / 10'9, 8.5 / 10'9, 8.4 / I0'9, 8.3 / I0’9, 8.2 / 10'9, 8.1 / 10-9, 8.0xl0‘9, 7.9 / 7.8xl0’9, 7.7 / 10'9, 7.6 / 10'9, 7.5 pr 7.4 / 10'9, 7.3 / 10'9, 7.2xl0‘9, 7.1X10-9, 7. Ox IO"9, 6.9xl0"9, 6.8 / 10'9, 6.7 / 10'9, 6.6 / 10'9, 6. / 10'9, 6.4x]O'9, 6.3xl0‘9, 6.2 / 10'9, 6.1 / lCr9, 6.0 / lCr9, 5.9 / 10'9, 5.8 / 10'9, 5.7 / 10'9, 5.6 / 10'9, 5.5 / 10'9, 5.4 / 10'9, 5.3 / 10-9, 5.2 / 10’9, 5. LIO’9, 5.0 / 10'9, 4.9 / fi. 4.8 / 10'9, 4.7 / 10'9, 4.6xl0'9, 4.5 / 10'9, 4.4 / 10'9, 4.3 - IO'9, or4.2xl0’9, 4.1 / 10'9, 4.0 / I0’9, 3.9 / 10'9, 3.8 / 10'9, 3.7 / 10'9, 3.6 / 10’9, 3.5 / 10'9, 3.4 / 10’9, 3.3 / J0'9, 3.2 / 10'9, 3. LIO'9, 3.0 / I0"9, 2.9 / I0'9, 2.8 / 10’9, 2.7 / IO’9, 2.6 / 1 O'9, 2.5 / 10'9, 2.4 / 10'9, 2.3 / 10'9, 2.2 / 10'9, 2. LIO'9, 2.0 / lCr9, 1.9 / 10'9, and 1.8 / 10'9M) in a bivalent format (i.e., a construct comprising two anti-Col2 ISVDs).

[0124] In certain embodiments, the first ISVD inhibits binding of IL-1 p to Interleukin I Receptor Type 1 (IL-1R1) with an ICso that is between 80-340 nM (e.g., between 80 and 85 nM, between 85 and 90 nM, between 90 and 95 nM, between 95 and 100 nM, between 100 and 105 nM, between 105 and 110 nM, between 110 and 115 nM, between 115 and 120 nM, between 120 and 125 nM, between 125 and 130 nM, between 130 and 135 nM, between 135 and 140 nM, between 140 and 145 nM, between 145 and 150 nM, between 150 and 155 nM, between 155 and 160 nM, between 160 and 165 nM, between 165 and 170 nM, between 170 and 175 nM, between 175 and 180 nM, between 180 and 185 nM, between 185 and 190 nM, between 190 and 195 nM, between 195 and 200 nM, between 200 and 205 nM, between 205 and 210 nM, between 210 and 215 nM, between 215 and 220 nM, between 220 and 225 nM, between 225 and 230 nM, between 230 and 235 nM, between 235 and 240 nM, between 240 and 245 nM, between 245 and 250 nM, between 250 and 255 nM, between 255 and 260 nM, between 260 and 265 nM, between 265 and 270 nM, between 270 and 275 nM, between 275 and 280 nM, between 280 and 285 nM, between 285 and 290 nM, between 290 and 295 nM, between 295 and 300 nM, between 300 and 305 nM, between 305 and 310 nM, between 31032 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOand 315 nM, between 315 and 320 nM, between 320 and 325 nM, between 325 and 330 nM, between 330 and 335 nM, betw-een 335 and 340 nM).

[0125] In certain embodiments, tire bispecific polypeptide is cross-reactive with human IL-1β and IL- 1 p of at least one other mammalian species. In certain embodiments, the bispecific polypeptide is cross-reactive with human Col2 and Col2 of at least one other mammalian species. In certain embodiments, the at least one other mammalian species is a rodent, or a non-human primate. In certain embodiments, the rodent is a rat. In certain embodiments, the non-human primate is a rhesus macaque.

[0126] In certain embodiments, the bispecific polypeptide has a melting temperature of at 50cC or greater (e.g., 50°C, 1°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C, 69°C, 70°C, 71°C, 72°C, 73°C, 74 °C, 75°C, 76°C, 77°C, 78°C, 79°C, 80°C, 81°C, 82°C, 83°C, 84°C, 85°C, or greater).

[0127] In certain embodiments, the bispecific polypeptide has an isoelectric point (pl) of greater than 6, greater than 7, or greater than 8. In certain embodiments, the bispecific polypeptide has a pl of greater than 6 (e.g., 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9,4, 9,5, 9,6, 9,7, 9,8, 9,9, 10.0, or greater). In certain embodiments, the bispecific polypeptide has a pl of greater than 7 (e.g., 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, or greater). In certain embodiments, the bispecific polypeptide has a pl of greater than 8 (e.g., 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, or greater).

[0128] In certain embodiments, the first ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL-1 [3. In certain embodiments, the reference antibody comprises an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to any one of SEQ ID NOs: 10-182 and 6813-6817. In certain embodiments, the first ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL- 1(3, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 10. In certain embodiments, the first ISVD competes for binding with an anti-IL-tp reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 11. In certain embodiments, the first ISVD competes for binding with an anti-IL-l reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 12. In certain 33 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOembodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 13. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 14. In certain embodiments, the first ISVD competes for binding with an anti-IL-1 P reference antibody to an epitope of IL- 1 p, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 15. In certain embodiments, the first ISVD competes for binding with an anti-IL-1 p reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 16. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 17. In certain embodiments, the first ISVD competes for binding with an anti -IL- 1 P reference antibody to an epitope of IL- 1 P, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 18. In certain embodiments, the first ISVD competes for binding with an anti-IL-1 p reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 19. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 20. In certain embodiments, the first ISVD competes for binding with an anti -IL- 1 P reference antibody to an epitope of IL- 1 P, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 21. In certain embodiments, the first ISVD competes for binding with an anti-IL-1 p reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 22. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL- ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 23. In certain embodiments, the first ISVD competes for binding with an anti -IL- 1 P reference antibody to an epitope of IL- 1 P, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 24. In certain embodiments, the first ISVD competes for binding with an anti-IL-1 p reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 25. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL- ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 26. In certain embodiments, the first ISVD competes for binding with an anti-IL-1 P reference antibody to an epitope of IL- 1 p, wherein the 34 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOreference antibody comprises an amino acid sequence of SEQ ID NO: 27. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 28. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL- ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 29. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 30. In certain embodiments, tire first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 31. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL- ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 32. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 33. In certain embodiments, tire first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 34. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL- ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 35. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 36. In certain embodiments, tire first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 37. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 38. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 39. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 40. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 41. In certain embodiments, the first ISVD competes 35 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOfor binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 42. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL- Ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 43. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wlierein the reference antibody comprises an amino acid sequence of SEQ ID NO: 44. In certain embodiments, the first ISVD competes for binding w ith an anti-IL-lp reference antibody to an epitope of IL-1 p, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 45. In certain embodiments, the first ISVD competes for binding with an anti-IL-1 P reference antibody to an epitope of IL- 1 p, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 46. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wlierein the reference antibody comprises an amino acid sequence of SEQ ID NO: 47. In certain embodiments, the first ISVD competes for binding w ith an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 48. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, w herein the reference antibody comprises an amino acid sequence of SEQ ID NO: 49. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wlierein the reference antibody comprises an amino acid sequence of SEQ ID NO: 50. In certain embodiments, the first ISVD competes for binding w ith an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 51. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, w herein the reference antibody comprises an amino acid sequence of SEQ ID NO: 52. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wlierein the reference antibody comprises an amino acid sequence of SEQ ID NO: 53. In certain embodiments, the first ISVD competes for binding w ith an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 54. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, w herein the reference antibody comprises an amino acid sequence of SEQ ID NO: 55. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an 36 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOamino acid sequence of SEQ ID NO: 56. In certain embodiments, the first ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL- 1 P, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 57. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 58. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 59. In certain embodiments, the first ISVD competes for binding with an anti-IL-Ip reference antibody to an epitope of IL- 1 P, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 60. In certain embodiments, the first ISVD competes for binding with an anti-IL-Ip reference antibody to an epitope of IL- 1 p, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 61. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 62. In certain embodiments, the first ISVD competes for binding with an anti-IL-Ip reference antibody to an epitope of IL- 1 P, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 63. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 64. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 65. In certain embodiments, the first ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL- 1 P, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 66. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 67. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 68. In certain embodiments, the first ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL- 1 P, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 69. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 70. In certain embodiments, the first ISVD competes for binding with an anti- 37 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOIL- Ip reference antibody to an epitope of IL- Ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 71. In certain embodiments, the first ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of I -ip. wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 72. In certain embodiments, the first ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL- Ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 73. In certain embodiments, the first ISVD competes for binding with an anti- IL-lp reference antibody to an epitope of IL- Ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 74. In certain embodiments, the first ISVD competes for binding with an anti -IL- ip reference antibody to an epitope of IL- 1, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 75. In certain embodiments, the first ISVD competes for binding with an anti-IL-l reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 76. In certain embodiments, the first ISVD competes for binding with an anti- IL-lp reference antibody to an epitope of IL- Ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 77. In certain embodiments, the first ISVD competes for binding with an anti -IL- ip reference antibody to an epitope of IL- 1, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 78. In certain embodiments, the first ISVD competes for binding with an anti-IL-l reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 79. In certain embodiments, the first ISVD competes for binding with an anti- IL-lp reference antibody to an epitope of IL- Ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 80. In certain embodiments, the first ISVD competes for binding with an anti -IL- ip reference antibody to an epitope of IL- 1, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 81. In certain embodiments, the first ISVD competes for binding with an anti-IL-l reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 82. In certain embodiments, the first ISVD competes for binding with an anti- IL-lp reference antibody to an epitope of IL- Ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 83. In certain embodiments, the first ISVD competes for binding with an anti -IL- ip reference antibody to an epitope of IL- 1, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 84. In certain embodiments, the first ISVD competes for binding with an anti-IL-l reference antibody to an epitope of IL- 1 p, wherein the reference antibody comprises an amino acid sequence of 38 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOSEQ ID NO: 85. In certain embodiments, the first ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL- Ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 86. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 87. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 88. In certain embodiments, the first ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL- Ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 89. In certain embodiments, the first ISVD competes for binding with an anti-IL-l reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 90. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 91. In certain embodiments, the first ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL- Ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 92. In certain embodiments, the first ISVD competes for binding with an anti -IL- Ip reference antibody to an epitope of IL- ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 93. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 94. In certain embodiments, the first ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL- Ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 95, In certain embodiments, the first ISVD competes for binding with an anti-IL-l reference antibody to an epitope of IL- ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 96. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 97. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 98. In certain embodiments, the first ISVD competes for binding with an anti-IL-l reference antibody to an epitope of IL- ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 99. In certain embodiments, the first ISVD competes for binding with an anti-IL-lp reference antibody to 39 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOan epitope of IL- 1(3, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 100. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL- 1 3, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 101. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL- 1, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 102. In certain embodiments, the first ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL- 1(3, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 103. In certain embodiments, the first ISVD competes for binding with an anti-IL-tp reference antibody to an epitope of IL- Ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 104. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL- 1, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 105. In certain embodiments, the first ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL- 1(3, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 106. In certain embodiments, the first ISVD competes for binding with an anti-IL-tp reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 107. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL- 1, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 108. In certain embodiments, the first ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL- 1(3, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 109. In certain embodiments, the first ISVD competes for binding with an anti-IL-tp reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 110. In certain embodiments, the first ISVD competes for binding with an anti -IL- Ip reference antibody to an epitope of IL-i, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 111. In certain embodiments, the first ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL- 1(3, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 112. In certain embodiments, the first ISVD competes for binding with an anti-IL-tp reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 113. In certain embodiments, the first ISVD competes for binding with an anti -IL- Ip reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 114. In certain 40 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOembodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 115. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 116. In certain embodiments, the first ISVD competes for binding with an anti-IL-1 P reference antibody to an epitope of IL- 1 p, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 117. In certain embodiments, tire first ISVD competes for binding with an anti-IL-1 p reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 118. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 119. In certain embodiments, the first ISVD competes for binding with an anti-IL-1 P reference antibody to an epitope of IL- 1 P, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 120. In certain embodiments, the first ISVD competes for binding with an anti-IL-1 p reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 121. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL- ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 122. In certain embodiments, the first ISVD competes for binding with an anti-IL-1 P reference antibody to an epitope of IL- 1 P, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 123. In certain embodiments, the first ISVD competes for binding with an anti-IL-1 p reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 124. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL- ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 125. In certain embodiments, the first ISVD competes for binding with an anti-IL-1 P reference antibody to an epitope of IL- 1 P, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 126. In certain embodiments, the first ISVD competes for binding with an anti-IL-1 p reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 127. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL- ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 128. In certain embodiments, the first ISVD competes for binding with an anti-IL-1 P reference antibody to an epitope of IL- 1 p, wherein the 41 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOreference antibody comprises an amino acid sequence of SEQ ID NO: 129. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 130. In certain embodiments, the first ISVD competes for binding with an anti- IL-1β reference antibody to an epitope of IL- ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 131. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 132. In certain embodiments, tire first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 133. In certain embodiments, the first ISVD competes for binding with an anti- IL-1β reference antibody to an epitope of IL- ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 134. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 135. In certain embodiments, tire first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 136. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL- ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 137. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 138. In certain embodiments, tire first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 139. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 140. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 141. In certain embodiments, tire first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 142. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 143. In certain embodiments, the first ISVD competes 42 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOfor binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 144. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL- Ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 145. In certain embodiments, tire first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wfierein the reference antibody comprises an amino acid sequence of SEQ ID NO: 146. In certain embodiments, the first ISVD competes for binding w ith an anti-IL-lp reference antibody to an epitope of IL-1 p, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 147. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL- ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 148. In certain embodiments, tire first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wfierein the reference antibody comprises an amino acid sequence of SEQ ID NO: 149. In certain embodiments, the first ISVD competes for binding w ith an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 150. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epi tope of IL-1 P, w herein the reference antibody comprises an amino acid sequence of SEQ ID NO: 151. In certain embodiments, tire first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wfierein the reference antibody comprises an amino acid sequence of SEQ ID NO: 152. In certain embodiments, the first ISVD competes for binding w ith an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 153. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epi tope of IL-1 P, w herein the reference antibody comprises an amino acid sequence of SEQ ID NO: 154. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wfierein the reference antibody comprises an amino acid sequence of SEQ ID NO: 155. In certain embodiments, the first ISVD competes for binding w ith an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 156. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epi tope of IL-1 P, w herein the reference antibody comprises an amino acid sequence of SEQ ID NO: 157. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an 43 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOamino acid sequence of SEQ ID NO: 158. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 159. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 160. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 161. In certain embodiments, the first ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL- 1 P, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 162. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 163. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 164. In certain embodiments, the first ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL- 1 P, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 165. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 166. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 167. In certain embodiments, the first ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL- 1 P, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 168. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 169. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 170. In certain embodiments, the first ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL- 1 P, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 171. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 172. In certain embodiments, tire first ISVD competes for binding with an anti- 44 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOIL- Ip reference antibody to an epitope of IL- Ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 173. In certain embodiments, the first ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL-i, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 174. In certain embodiments, the first ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL- Ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 175. In certain embodiments, the first ISVD competes for binding with an anti- IL-lp reference antibody to an epitope of IL- Ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 176. In certain embodiments, the first ISVD competes for binding w ith an anti -IL- ip reference antibody to an epitope of IL-i, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 177. In certain embodiments, the first ISVD competes for binding with an anti-IL-l reference antibody to an epitope of IL- Ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 178. In certain embodiments, the first ISVD competes for binding with an anti- IL-lp reference antibody to an epitope of IL- Ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 179. In certain embodiments, the first ISVD competes for binding with an anti -IL- ip reference antibody to an epitope of IL-i, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 180. In certain embodiments, the first ISVD competes for binding with an anti-IL-l reference antibody to an epitope of IL- Ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 181. In certain embodiments, the first ISVD competes for binding with an anti- IL-lp reference antibody to an epitope of IL- Ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 182. In certain embodiments, the first ISVD competes for binding with an anti -IL- ip reference antibody to an epitope of IL-i, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6813. In certain embodiments, the first ISVD competes for binding with an anti-IL-l reference antibody to an epitope of IL- Ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6814. In certain embodiments, the first ISVD competes for binding with an anti- IL-lp reference antibody to an epitope of IL- Ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6815. In certain embodiments, the first ISVD competes for binding with an anti -IL- ip reference antibody to an epitope of IL-i, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6816. In certain embodiments, the first ISVD competes for binding with an anti-IL-l reference antibody to an epitope of IL- 1 p, wherein the reference antibody comprises an amino acid sequence of 45 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOSEQ ID NO: 6817. In certain embodiments, the first ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL- Ip, wherein the reference antibody is canakinumab. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL- Ip, wherein the reference antibody is rilonacept. In certain embodiments, the first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody is lutikizumab (ABT-981).

[0129] In certain embodiments, the second ISVD competes for binding with a reference anti-Co!2 antibody to an epitope of Col2. In certain embodiments, the reference antibody comprises an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to any one of SEQ ID NOs: 356-477 and 6928-6951. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 356. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 357. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 358. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 359. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 360. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 361. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 362. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 363. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 364. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of 46 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOSEQ ID NO: 365. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 366. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 367. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 368. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 369, In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 370. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 371. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 372, In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 373. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 374. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 375, In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 376. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 377. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 378, In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 379. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to 47 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOan epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 380. In certain embodiments, the second ISVD competes for binding with an anti-CoI2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 381. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 382. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 383. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wdierein the reference antibody comprises an amino acid sequence of SEQ ID NO: 384. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 385. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 386. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wdierein the reference antibody comprises an amino acid sequence of SEQ ID NO: 387. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 388. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 389. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wdierein the reference antibody comprises an amino acid sequence of SEQ ID NO: 390. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 391. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 392. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wdierein the reference antibody comprises an amino acid sequence of SEQ ID NO: 393. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 394. In certain 48 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOembodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 395. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein die reference antibody comprises an amino acid sequence of SEQ ID NO: 396. In certain embodiments, the second IS VD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 397. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 398. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein die reference antibody comprises an amino acid sequence of SEQ ID NO: 399. In certain embodiments, the second IS VD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 400. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 401. In certain embodiments, the second ISVD competes for binding with an anti-CoI2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 402. In certain embodiments, the second IS VD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 403. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 404. In certain embodiments, the second ISVD competes for binding with an anti-CoI2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 405. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 406. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 407. In certain embodiments, the second ISVD competes for binding with an anti-CoI2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 408. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the 49 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOreference antibody comprises an amino acid sequence of SEQ ID NO: 409. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 410. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 411. In certain embodiments, the second ISVD competes for binding with an anti-CoI2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 412. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 413. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 414. In certain embodiments, the second ISVD competes for binding with an anti-CoI2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 415. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 416. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 417. In certain embodiments, the second ISVD competes for binding with an anti-CoI2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 418. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 419. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 420. In certain embodiments, the second ISVD competes for binding with an anti-CoI2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 421. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 422. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 423. In certain embodiments, tire second ISVD 50 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOcompetes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein tlie reference antibody comprises an amino acid sequence of SEQ ID NO: 424. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 425. In certain embodiments, tire second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 426. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein tlie reference antibody comprises an amino acid sequence of SEQ ID NO: 427. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein tlie reference antibody comprises an amino acid sequence of SEQ ID NO: 428. In certain embodiments, tlie second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 429. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 430. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 431. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 432. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 433. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 434. In certain embodiments, tlie second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 435. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 436. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 437. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises 51 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOan amino acid sequence of SEQ ID NO: 438. in certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 439. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 440. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 441. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 442. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 443. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 444. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 445. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 446. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 447. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 448. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 449. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 450. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 451. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 452. In certain embodiments, tire second ISVD competes for binding with an 52 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOanti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 453. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 454. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 455. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 456. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 457. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 458. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 459. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 460. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 461. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 462. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 463. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 464. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 465. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 466. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of 53 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOSEQ ID NO: 467. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 468. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 469. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 470. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 471, In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 472. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 473. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 474, In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 475. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 476. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 477, In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6928. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6929. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6930. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6931. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to 54 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOan epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6932. In certain embodiments, the second ISVD competes for binding with an anti-CoI2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6933. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6934, In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6935. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6936. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6937, In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6938. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6939. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6940. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6941. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6942. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6943, In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6944. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6945. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6946. In certain 55 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOembodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6947. In certain embodiments, tire second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6948. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6949. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6950. In certain embodiments, the second ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6951. In certain embodiments, the second ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises any one of the anti-Co!2 avimers described in Hulme et al. J. Ortho. Res. 36(4):1238-47 (2017) (e.g., anti-Col2 avimer M26).

[0130] Disclosed herein, in certain embodiments, is a pharmaceutical composition comprising the bi specific polypeptide of any one of the foregoing aspects and embodiments, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0131] Disclosed herein, in certain embodiments, is a nucleic acid encoding the bispecific polypeptide of any one of the foregoing aspects and embodiments.

[0132] Disclosed herein, in certain embodiments, is an expression vector comprising the nucleic acid of the foregoing aspect.

[0133] Disclosed herein, in certain embodiments, is a host cell comprising the nucleic acid or the expression vector of the foregoing aspects,

[0134] Disclosed herein, in certain embodiments, is a method of treating a disease or disorder in a subject, the method comprising administering to the subject the bispecific polypeptide or the pharmaceutical composition of the foregoing aspects and embodiments. In certain embodiments, the disease or disorder is an inflammatory disease or disorder. In certain embodiments, the inflammatory disease or disorder is an IL-lp-mediated disease or disorder. In certain embodiments, the IL- Ip-mediated inflammatory disease or disorder is osteoarthritis. In certain embodiments, the IL-1β-mediated inflammatory disease or disorder is refractory' gout. In certain embodiments, the IL-1β-mediated inflammatory disease or disorder is non-infectious uveitis.56 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO

[0135] In certain embodiments, the bispecific polypeptide or the pharmaceutical composition of the foregoing aspects and embodiments are administered by way of systemic administration. In certain embodiments, the bispecific polypeptide or the pharmaceutical composition of the foregoing aspects and embodiments are administered by way of local administration. In certain embodiments, local administration comprises intra-articular administration.

[0136] Disclosed herein, in certain embodiments, is a bispecific agent, comprising: (a) at least one first means for specifically binding to IL- Ip; and (b) at least one second means for specifically binding to Col2. In certain embodiments, the bispecific agent comprises two second means for specifically binding to Col2. In certain embodiments, the at least one first means for specifically binding to IL- Ip and the at least one second means for specifically binding to Col2 are connected by a linker.

[0137] Disclosed herein, in certain embodiments, is an ISVD that specifically binds to IL-1. In certain embodiments, the ISVD is a VHH.

[0138] In certain embodiments, the ISVD comprises a CDR1 comprising an amino acid sequence of any one of SEQ ID NOs: 2155-2327 and 6863-6867, a CDR2 comprising an amino acid sequence of SEQ ID NO: 2501-2673 and and 6873-6877, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 2847-3019 and and 6883-6887.

[0139] In certain embodiments, the ISVD comprises an amino acid sequence having at least 80% (e.g, at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to any one of SEQ ID NOs: 10-182 and 6813-6817. In certain embodiments, the ISVD comprises an amino acid sequence having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to any one of SEQ ID NOs: 10-182 and 6813-6817. In certain embodiments, the ISVD comprises an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to any one of SEQ ID NOs: 10-182 and 6813-6817, In certain embodiments, the ISVD comprises an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or more) sequence identity to any one of SEQ ID NOs: 10-182 and 6813-6817. In certain embodiments, the ISVD comprises an amino acid sequence having 100% sequence identity to any one of SEQ ID NOs: 10-182 and 6813-6817. In certain embodiments, the ISVD consists of an amino acid sequence having 100% sequence identity to any one of SEQ ID NOs: 10-182 and 6813-6817.57 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO

[0140] In certain embodiments, the 1SVD specifically binds to IL- 1 p with a koff between 1.0xl04s and 2.2x 1 O^s"1(e.g., l. Ox lQ-'s"1, 9. fir's4. 9.8x10, 9.7x l0"2s“5, 9.6xl0’2s, 9.5x]0"2s49.4 fir’s '. 9.3x ] (T, Jx lO', 9.1 x l0"2s"1,. OxlO’1, 8.9x 10’2s48.8x 10"2s'1, 8.7x l0"2s"1, S.bx lO'1, S. Sx lO', 8.4 fir's"'. SJx lO', S^x lO’, S. l x lO', 8.0x l0-2s"!, y^x lO', 7.8X 10"2S"!, 7.7X 10"2S"1, 7.6x l0-2s"1, 7. x l0"2s"1, 7.4x l0"2s"1, 7.3x 10"2s"1, 7.2x l0"2s-', 7.1 x ] 0"2s"1, 7.0x l0"2s"i, 6.9x 10"2s"!, b. Sx ULs"1, 6.7x 10"2s"!, Ax ULs"1, e.sx io-, 6.4x io-2s4e.sx io', jx io-, e. i x io-, e.oxio, 5.9xiO"2s, 5.8x i o-, S x lO'1, P.ex lO'1, 5.5 fir's"'. S^x lO', o. Sx lO’, S x lO', o. l x lO’, S. Ox lO'1, 4.9x l0"2s"!, 4.8X 10"2S"1, 4.7x l0"2s4, 4.6x l0"2s"1, 4.5> < 10"2s'], 4.4 fir s" L 4.3x 10", 4.2x ] O’V, 4 J fir's"1. 4.0x ] O’, S. x lO’1, 3.8x lO’1, 3.7x lO’2s, SAxlO’1, S. Sx lO’V, 3.4 fir s"1. SJx lO-, 3.2X10-1, 3.1 xlO"2s, 3.0xl0"2s, 2.9x l 0"2s"1, 2.8x 10"2s'1, 2.7x l0"2s"’, 2.6x l0"2s"1, 2.5 x W, 2.4* W1, 2.3x l0"2s"i, 2.2 fir's"'. 2.1 x l0"2s"i, 2.0 fir 's4. 1.9xlO"2s41.8x lO"2s4, IJxlO^s"1, l.bx lO’1, 1.5x ] 0"2s"1, ].4x lO"2s4, 1.3x 10"2s"\ IJx lO-1, 1.1 x l O’, l. OxlOV, 9.9x l0"3s"1, 9.8x l0"3s"i, 9.7x l0"3s"1, 9.6x l0"3s"i, 9.5x lO"3s49.4x l0"3s"1, 9.3X 10-1, 9.2x l0"3s"1,. l x lO', 9.0x l0"3s"1, 8.9 l0"3s48.8x 10"3s"’, 8.7x l0"3s"1, 8.6x l0"3s"’, 8. x l0"3s"!, S^x lO’1, 8.3x l0"3s"!, S^x lO’1, 8.1 x l0"3s"!, S. Ox R s"1, 7.9> fir. 7.8x l0-3s"1, 7.7x lO"3s4, 7.6x l0"3s"1, 7.5x l0"3s4, 7.4x l 0"3s"1, 7.3x 10", 7.2x 10'V, 7. I x lO"3s"1, 7.0x l0"3s"1, b. x lO’V, 6.8x 10', Jx lO’V, 6.6x 10', 6.5x l0"3s"!, e. x lO', 6.3 X 10"3S"!, ejx lO', 6.1 x l0"3s"], 6.0x l0"3s"1, 5.9x l0"3s"], 5.8x 10"3s"1, SJx lO’1, 5.6x l 0"3s"1, S x lO’1, 5.4x l0"3s"!, SJx U’r, 5.2x l0"3s"!, S. l x U’r, S. Ox lO^s"1, 4.9x l0"3s"1, 4.8 fir 's.4. 4.7x l0"3s"1, 4.6x l0"3s'1, 4.5x l 0"3s"1, 4.4 fir;s"'. 4.3x 10", 4.2x l0"3s"1, 4.1 x l0"3s"1,. Ox lO’1, S. x lO', S. Sx lO’V, SJx lO'1, S.ex lO’V, SJx lO’1, 3.4x l0"3s4, SJx lO’1, 3.2x l0"3s4, 3.1 x l0"3s"1, 3.0x l0"3s"’, 2.9x l0"3s"1, 2.8x 10"3s4, 2.7x l 0"3s"1, 2.6x lO"3s4, 2.5x l0"3s"!, 2.4x l0"3s"i, 2.3x l0"3s"!, 2.2x l0"3s"i, 2.1 fir's '. 2.0x l0“3s"1, l. x lO', I. Sx lO’1, I JxlO'1, l. Ox lO’1, l.ox lO-, l^x l O’, 1.3x 10"3s"1, 1.2x l0"3s"’, l. l x lO'V, 1.0x l0"3s"’, 9.9x l0"4s"!,. SxlOY, 9.7x l0"4s"!,.bx lO’V, 9.5x lO‘4s4, ^x lO’, 9.3 fir 's4. ^xlO’, 9.1 x lO"4s4, 9.0x l 0"4s"1, 8.9x l0"4s4, 8.8x 10", S^xlO, 8.6x10’, SJxlOV, 8.4x 10’, S. Sx lO’, 8.2x 10’, S.lxlO’, S. Ox lO', 7.9x l0"4s"1, 7.8x l0"4s"1, 7.7x l0"4s"1, 7.6x l0"4s"1, 7.5x l0"4s"1, 7.4x l0"4s"1, 7.3x 10"4s'], 7.2x l0"4s"1, 7.1 x l0"4s"’, 7.0 fir’s"'.. Ox lO’V, 6.8 fir's"'. 6.7x l0"4s"i, 6.6x l0"4s"‘, Jx lO’V, 6.4 fir 's4. Jx lO-, 6.2x lO"4s4, 6.1 x l0"4s"1, 6.0x l0"4s4, 5.9x l 0"4s"1, 5.8x 10"4s-1, SJx lO’, S. x lO-V, S x lO’V, S^x lO-V, S. Sx lO’, S^x lO-V, S.lxlO’, S. Ox lO’, 4.9x l0"4s"1,. Sx lO-, 4.7x l0"4s"1, 4.6x l0"4s"1, 4.5 fir's"1. 4.4x l0"4s"1, 4.3x 10"4s"1, 4.2x l0"4s"’, 4.1 x l0"4s"1, 4.0x l0"4s"i, 3.9x l0"4s"!, S. Sx lO’, 3.7 fir's"'. S^xlO1,58 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO3.5x 10V, 3.4x10V, 3.3X10'V, 3.2x10, 3.1xl0V, 3.0xl0V, 2.9xl0V, 2.8x10’ V, 2.7x10, 2.6x10V, 2.5 > dOV, 2.4xlO’V, 2.3xl0V, and 2.2xlO’ ).

[0141] In certain embodiments, the ISVD specifically binds to IL- 1 p with a KD of between l.lx 10’7M and 2.4x IO’10M (e.g., l.lxlO’7, l. OxlO’7, 9.9xl0“8, 9.8xl0“8, 9.7xl0’8, 9.6xl0’8, 9.5 x IO’8, 9.4xl0’8, 9.3 xlO’8, 9.2xl0’8, 9. lx IO’8, 9. Ox IO’8, 8.9> 10“8, 8.8xlO’8, 8.7xl0’8, 8.6xl0’8, 8.5xlO’s, 8.4xl0"8, 8.3xlO’8, 8,2> < IO"8, 8, LIO'8, 8.0xJ0“8, 7.9xJ0“8, 7.8xl0"8, 7.7xl0’8, 7.6xl0’8, 7.5xlCr8, 7.4xl0“8, 7.3> <10'8, 7.2x]0’8, 7. LI0’8, 7.0x]0“8, 6.9xl0’8, 6.8xl0’8, 6.7xl0’8, 6.6 hr:":. 6.5 x IO’8, 6.4xl0’8, 6.3 x IO’8, 6.2xl0’8, 6. lx IO’8, 6.0xl0’8, 5.9xl0’8, 5.8xlO’8, 5.7 hr'"'. 5.6xl0’8, 5.5xl0“8, 5.4xl0’8, 5.3xl0’8, 5.2xl0’8, 5. LIO'8, 5. Oxl O’8, 4.9x] O’8, 4.8xl0’8, 4.7xl0’8, 4.6xl0’8, 4.5 xlO"8, 4.4xl0"8, 4.3 xlO"8, 4 2 IO'8.4. LI0'8, 4.0xl0’8, 3.9xl0’8, 3.8xlO’8, 3.7xl0’8, 3.6xl0’8, 3.5xlO’8, 3.4xl0’8, 3.3xlO’8, 3.2x IO’8, 3.1 x IO’8, 3. Ox 10“8, 2.9x IO’8, 2.8x IO'8, 2.7x IO'8, 2.6 IO’8, 2.5x 10“8, 2.4x 10“s, 2.3xl0’8, 2.2xl0’8, 2. L10"8, 2.0xl0’8, 1.9xl0’8, 1.8xlO’8, 1.7x]0’8, 1.6xJ0’8, 1.5xlO’8, 1.4xl0’8, 1.3xlO’8, 1.2xl0’8, l.lxlO’8, l. OxlO’8, 9.0xl0’9, 8.9xl0’9, 8.8x]0“9, 8.7xl0"9, 8.6xl0’9, 8.5xl0’9, 8.4 hr9. 8.3xl0’9, 8.2xl0“9, 8. L10“9, 8.0xl0’9, 7.9xl0“9, 7.8xl0'9, 7.7xl0’9, 7.6xl0’9, 7.5 hr9. 7.4xl0’9, 7.3 xlO’9, 7.2xl0’9, 7. L10“9, 7.0xl0’9, 6.9xl0’9, 6.8xl0’9, 6.7xl0’9, 6.6xl0’9, 6.5xl0’9, 6.4xl0’9, 6.3xl0’9, 6.2xl0"9, 6.1xl0’9, 6.0xl0’9, 5.9xl0’9, 5.8xl0’9, 5.7xl0’9, 5.6xl0’9, 5.5xl0’9, 5.4xl0’9, 5.3xl0’9, 5.2xl0“9, 5. L10’9, 5.0xl0’9, 4.9xl0’9, 4.8xl0’9, 4.7xl0“9, 4.6xl0’9, 4.5 x IO’9, 4.4xl0’9, 4.3 xlO’9, 4.2x 10’9, 4. IO"9, 4.0xl0’9, 3.9xl0’9, 3.8xl0’9, 3.7xl0’9, 3.6xl0“9, 3.5x]0’9, 3.4xl0’9, 3.3xl0’9, 3.2xl0’9, 3. lx IO’9, 3.0xl0’9, 2.9xl0’9, 2.8xl0’9, 2.7xl0’9, 2.6x0“9, 2.5xl0’9, 2.4xl0’9, 2.3x10"9, 2.2xl0’9, 2.1xl0’9, 2.0xl0’9, 1.9xl0’9, 1.8'xlO’9, 1.7xl0’9, 1.6xl0’9, 1.5xl0’9, 1.4xl0’9, 1.3xl0’9, 1.2xl0’9, l.lxlO’9, l. OxlO’9, 9.9xl0’l°, 9.8xl0’l°, 9.7xl0’l°, 9.6xl0’l°, 9.5xl0’l°, 9.4x10’’°, 9.3x10’’°, 9.2x10’’°, 9.1x10’’°, 9.0x10’’°, 8.9x10’’°, 8.8xlO’10, 8.7xlO’10, 8.6xlO’10, 8.5xlO’10, 8.4x10’’°, 8.3x10’’°, 8.2x10’’°, 8.1 x10’’°, 8.0x10’’°, 7.9x10’’°, 7.8x10’’°, 7.7x10’’°, 7.6x10’’°, 7.5x10’’°, 7.4x10’’°, 7.3x10’’°, 7.2x10’’°, 7.1x10’’°, 7.0x10’’°, 6.9x10’’°, 6.8x10’’°, 6.7x10’’°, 6.6x10’’°, 6.5x10’’°, 6.4x10’’°, 6.3x10’’°, 6.2x10’’°, 6.1x10’’°, 6.0x10"’°, 5.9x10"’°, 5.8x10’’°, 5.7x10"’°, 5.6x10"’°, 5.5x10"’°, 5.4x10"’°, 5.3x10"’°, 5.2x10"’°, 5.1x10"’°, 5.0x10"’°, 4.9x10"’°, 4.8x10"’°, 4.7x10"’°, 4.6x10"’°, 4.5x10"’°, 4.4x10"’°, 4.3x10"’°, 4.2x10"’°, 4.1x10"’°, 4.0x10"’°, 3.9x10"’°, 3.8x10"’°, 3.7x10"’°, 3.6x10"’°, 3.5x10"’°, 3.4x10"’°, 3.3x10"’°, 3.2x10"’°, 3.1x10“’°, 3.0x10“’°, 2.9x10“’°, 2.8x10“’°, 2.7x10“’°, 2.6x10“’°, 2.5x10“’°, and 2.4x10“’° M), as measured by SPR

[0142] In certain embodiments, the ISVD inhibits binding of IL- 1 [3 to IL-1R1 with an ICso that is between 80-340 nM (e.g., betw een 80 and 85 nM, between 85 and 90 nM, between 9059 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOand 95 nM, between 95 and 100 nM, between 100 and 105 nM, between 105 and 110 nM, between 110 and 115 nM, between 115 and 120 nM, between 120 and 125 nM, between 125 and 130 nM, between 130 and 135 nM, between 135 and 140 nM, between 140 and 145 nM, between 145 and 150 nM, between 150 and 155 nM, between 155 and 160 nM, between 160 and 165 nM, between 165 and 170 nM, between 170 and 175 nM, between 175 and 180 nM, between 180 and 185 nM, between 185 and 190 nM, between 190 and 195 nM, between 195 and 200 nM, between 200 and 205 nM, between 205 and 210 nM, between 210 and 215 nM, between 215 and 220 nM, between 220 and 225 nM, between 225 and 230 nM, between 230 and 235 nM, between 235 and 240 nM, between 240 and 245 nM, between 245 and 250 nM, between 250 and 255 nM, between 255 and 260 nM, between 260 and 265 nM, between 265 and 270 nM, between 270 and 275 nM, between 275 and 280 nM, between 280 and 285 nM, between 285 and 290 nM, between 290 and 295 nM, between 295 and 300 nM, between 300 and 305 nM, between 305 and 310 nM, between 310 and 315 nM, between 315 and 320 nM, between 320 and 325 nM, between 325 and 330 nM, between 330 and 335 nM, between 335 and 340 nM).

[0143] In certain embodiments, the ISVD is cross-reactive with human IL- 1 P and IL-1β of at least one other mammalian species. In certain embodiments, the at least one other mammalian species is a rodent or a non-human primate. In certain embodiments, the rodent is a rat. In certain embodiments, the non-human primate is a rhesus macaque.

[0144] In certain embodiments, the ISVD has a melting temperature of at least 50°C (e.g., at least 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, 61 °C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C, 69°C, 70°C, 71°C, 72°C, 73°C, 74°C, 75°C, 76°C, 77°C, 78°C, 79°C, 80°C, 81°C, 82°C, 83°C, 84°C, 85°C, or more).

[0145] In certain embodiments, the ISVD competes for binding with an anti -IL- 1 P reference antibody to an epitope ofIL-1β. In certain embodiments, the anti -IL- ip reference antibody comprises an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to any one of SEQ ID NOs: 10-182 and 6813-6817. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 11. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 12. in certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference 60 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOantibody comprises an amino acid sequence of SEQ ID NO: 13. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 14. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 15. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 16. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 17, In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 18. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 19. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 20. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 21. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 22. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 23. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 24. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 25. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 26. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 27. In certain embodiments, the ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL-lp, wherein the reference antibody comprises an 61 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOamino acid sequence of SEQ ID NO: 28. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 29. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 30. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 31. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 32. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, w herein the reference antibody comprises an amino acid sequence of SEQ ID NO: 33. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 34. In certain embodiments, the ISVD competes for binding wdth an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 35. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, w herein the reference antibody comprises an amino acid sequence of SEQ ID NO: 36. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 37. In certain embodiments, the ISVD competes for binding w ith an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 38. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, w herein the reference antibody comprises an amino acid sequence of SEQ ID NO: 39. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 40. In certain embodiments, the ISVD competes for binding w ith an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 41. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 42. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of 62 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOSEQ ID NO: 43. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 44. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 45. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 46. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 47. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 48. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 49. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 50. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 51. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 52. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 53. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 54. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 55. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 56. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 57. In certain embodiments, the ISVD competes for binding w ith an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 58. In 63 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOcertain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 59. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 60. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 61. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 62. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 63. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 64. In certain embodiments, the ISVD competes for binding w ith an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 65. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 66. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 67. In certain embodiments, the ISVD competes for binding w ith an anti-IL-1β reference antibody to an epitope of IL-1β, w herein the reference antibody comprises an amino acid sequence of SEQ ID NO: 68. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 69. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 70. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, w herein the reference antibody comprises an amino acid sequence of SEQ ID NO: 71. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wLerein the reference antibody comprises an amino acid sequence of SEQ ID NO: 72. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, w herein the reference antibody comprises an amino acid sequence of SEQ ID NO: 73. In certain embodiments, the 64 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 74. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 75. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 76. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 77. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 78. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 79. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, w herein the reference antibody comprises an amino acid sequence of SEQ ID NO: 80. In certain embodiments, tire ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 81. In certain embodiments, the ISVD competes for binding w ith an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 82. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, w herein the reference antibody comprises an amino acid sequence of SEQ ID NO: 83. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 84. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, w herein the reference antibody comprises an amino acid sequence of SEQ ID NO: 85. In certain embodiments, the ISVD competes for binding w ith an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 86. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 87. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 88. In certain embodiments, the ISVD competes for 65 / 647IPTS / 200261047.5Attorney Docket: AVT-001WObinding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 89. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 90. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 91. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, w herein the reference antibody comprises an amino acid sequence of SEQ ID NO: 92. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 93. In certain embodiments, the ISVD competes for binding w ith an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 94. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, w herein the reference antibody comprises an amino acid sequence of SEQ ID NO: 95. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wLerein the reference antibody comprises an amino acid sequence of SEQ ID NO: 96. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 97. In certain embodiments, the ISVD competes for binding w ith an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 98. in certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 99. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 100. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, w herein the reference antibody comprises an amino acid sequence of SEQ ID NO: 101. in certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 102. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 103. In certain embodiments, the ISVD competes for binding with an anti-IL-1066 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOreference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 104. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 105. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 106. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 107. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 108. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 109. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 110. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 111. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 112. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 113. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 114. In certain embodiments, the ISVD competes for binding with an anti -IL- ip reference antibody to an epitope of IL- 1 p, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 115. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 116. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 117, In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 118. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody 67 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOto an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 119. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 120. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 121. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 122. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 123. In certain embodiments, tire ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 124. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 125. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 126. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 127. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 128. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 129, In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 130. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 131. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 132, In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 133. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β,68 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOwherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 134. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 135. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 136. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 137. in certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 138. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 139. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 140. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 141, In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 142. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 143. in certain embodiments, the ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL- ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 144, In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 145. In certain embodiments, the ISVD competes for binding with an anti-IL-1 P reference antibody to an epitope of IL- 1 P, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 146. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 147. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 148. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference 69 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOantibody comprises an amino acid sequence of SEQ ID NO: 149. in certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 150. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 151. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 152. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 153, In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 154. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 155. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 156, In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 157. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 158. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 159. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, w herein the reference antibody comprises an amino acid sequence of SEQ ID NO: 160. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 161. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 162. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 163. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an 70 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOamino acid sequence of SEQ ID NO: 164. In certain embodiments, the ISVD competes for binding with an anti -IL- ip reference antibody to an epitope of IL-i, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 165. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 166. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL- ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 167. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 168, In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 169. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope oflL-tp, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 170. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 171. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1, w herein the reference antibody comprises an amino acid sequence of SEQ ID NO: 172. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 173. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 174. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 175. In certain embodiments, the ISVD competes for binding with an anti-IL-lp reference antibody to an epitope of IL-lp, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 176. In certain embodiments, the ISVD competes for binding w ith an anti -IL- ip reference antibody to an epitope of IL- 1 p, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 177. In certain embodiments, the ISVD competes for binding w ith an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 178. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of 71 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOSEQ ID NO: 179. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL- ip, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 180. In certain embodiments, the ISVD competes for binding with an anti -IL- ip reference antibody to an epitope of IL-i, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 181. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope ofIL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 182. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6813. In certain embodiments, the ISVD competes for binding with an anti-IL-i reference antibody to an epitope of IL-lp, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6814. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6815. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6816. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6817. In certain embodiments, the ISVD competes for binding with an anti-IL-1 P reference antibody to an epitope of IL- 1 p, wherein the reference antibody is canakinumab. In certain embodiments, the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-i, wherein the reference antibody is rilonacept. In certain embodiments, tire first ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β, wdierein the reference antibody is lutikizumab (ABT-981).

[0146] In certain embodiments, tire ISVD further comprises an Fc region.

[0147] Disclosed herein, in certain embodiments, is an ISVD that specifically binds to Col2. In certain embodiments, the ISVD is a VHH.

[0148] In certain embodiments, the ISVD comprises a CDR1 comprising an amino acid sequence of any one of SEQ ID NOs: 5209-5330 and 6976-6999, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5453-5574 and 7024-7047, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5697-5818 and 7072-7095,

[0149] In certain embodiments. In certain embodiments, the ISVD comprises an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence 72 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOidentity to any one of SEQ ID NOs: 356-477 and 6928-6951. In certain embodiments, the ISVD comprises an amino acid sequence having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to any one of SEQ ID NOs: 356-477 and 6928-6951. In certain embodiments, the ISVD comprises an amino acid sequence having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to any one of SEQ ID NOs: 356-477 and 6928-6951. In certain embodiments, the ISVD comprises an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or more) sequence identity to any one of SEQ ID NOs: 356-477 and 6928-6951. In certain embodiments, the ISVD comprises an amino acid sequence having 100% sequence identity to any one of SEQ ID NOs: 356-477 and 6928-6951. In certain embodiments, the ISVD consists of an amino acid sequence having 100% sequence identity to any one of SEQ ID NOs: 356-477 and 6928-6951.

[0150] In certain embodiments, the ISVD specifically binds to Col2 with a koff between 1.2x10V1and 9.1x10V1(e.g., l.lxlo, l. O lOV1, 9.9x10V1, 9.8xl0'4s, 9.7x10V1, 9.6x10V1, 9.5x10V1, 9.4x10V, 9.3x10V, 9.2xl0'4, 9.1x10V1, 9.0x10V, 8.9x10V1, 8.8 KV1. 8.7x101, 8.6x10V1, 8.5x10V, 8.4x10V, 8.3x]0, 8.2xl0"4, 8.1x10V1, 8.0 10 V. 7.9x101, 7.8x10V1, 7.7x10V1, 7.6x10V1, 7.5x10V1, 7.4x10'4s'1, 7.3x10V1, 7.2x10V1, 7.1X10, 7.0xl0V!, 6.9x10V1, 6.8 h' f 6.7x10V1, 6.6x10V, 6.5x10V1, 6.4x10V, 6.3x10V1, 6.2x10V1, 6.1 x10V1, 6.0x10V1, 5.9x10'4s, 5.8x10V1, 5.7x10V1, 5.6xl0'V, 5.5x10V1, 5.4x10V, 5.3x10V1, 5.2x10V, 5.1x10V, 5.0x10V1, 4.9x10V1, 4.8x10V1, 4.7x10V, 4.6x10V1, 4.5x10V1, 4.4x10' V, 4.3x10V1, 4.2x10V1, 4.1x10V1, 4.0x10V, 3.9x10V1, 3.8x10V1, 3.7x10V1, 3.6x10V1, 3.5x10V, 3.4x10V1, 3.3x10V, 3.2x10V1, 3.1x10V1, 3.0x10V1, 2.9x10" V, 2.8x10V1, 2.7x10V1, 2.6x10V1, 2.5xlO'V, 2.4x10V1, 2.3xlO'V, 2.2x10V1, 2.1x10V, 2.0x10V1, 1.9x10V, 1.8x10V1, 1.7x10V1, 1.6x10V1, IVIOV, 1.4x10'4s, 1.3x10V, 1.2x10V1, l.lxlOV, l. OxlOV1, 9.9x10V1, 9.8x10V1, 9.7x10V1, 9.6x10, 9.5 x10V1, 9.4x101, 9.3 x10V1, 9.2x10 V, and 9.1x101) in a bivalent format (i.e., a construct comprising two anti-Col2 ISVDs).

[0151] In certain embodiments, the IS VD specifically binds to Col2 with a KD of between 4xl0"6M and I VIO'9M (e.g., 4.0xl0'6, 3.9xl0’6, 3.8xl0'6, 3.7xl0'6, 3.6x1 O'6, 3.5xl0'6, 3.4xl0“6, 3.3xl0'6, 3.2xl0'6, 3.1 xlO'6, 3.0xl0'6, 2.9xl0'6, 2.8xl0'6, 2.7xl0'6, 2.6xl0“6, 2.5xl0'6, 2.4xl0'6, 2.3xl0'6, 2.2xl0'6, 2.1xl0'6, 2.0xl0'6, IV IO'6, IVIO'6, 1.7xl0'6, 1.6xl0'6, 1.5xl0'6, 1.4xl0'6, 1.3xl0'6, 1.2.x IO'6, l.lxlO'6, 1.0> 10'6, 9.0xl0'7, 8.9xl0'7,73 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO8.8xl0'7, 8.7xl0'7, 8.6 hr’. 8.5xl0'7, 8.4xl0'7, 8.3xl0’7, 8.2x 10'7, 8.1xl0'7, 8.0 / 10'7, 7.9xl0“7, 7.8xl0'7, 7.7 hr’. 7.6 / 10'7, 7.5 / 10'7, 7.4xl0'7, 7.3xl0"7, 7.2xl0“7, 7.1xl0'7, 7.0xI0“7, 6.9x]0'7, 6.8xl0’7, 6.7 / 10'7, 6.6 / 10'7, 6.5 / 10'7, 6.4 / 10'7, 6.3zl0’7, 6.2 / 10'7, 6.1X10’7, 6.0xl0-7, 5.9xl0-7, 5.8X10'7, 5.7 / 10'7, 5.6 / 10'7, 5.5 10". 5.4 / 10'7, 5.3 / 10'7, 5.2x 10'7, 5.1 x IO'7, 5. Ox IO'7, 4.9x IO’7, 4.8x 10'7, 4.7x 10'7, 4.6 / IO'7, 4, 1 O'7. 4.4- 1 (5. 4.3xl0‘7, or4.2xl0"7M, 4.1 xj0'7, 4,0 Hr7. 3.9xl0’7, 3.8xl0'7, 3.7xl0’7, 3.6 / 10'7, 3.5x]0'7, 3.4xl0‘7, 3.3xl0'7, 3.2xl0"73.1zlO’7, 3.0 / I0'7, 2.9xI0'7, 2.8x]0'7, 2.7x]0'7, 2.6 / 10'7, 2.5xl0'7, 2.4X10'7, 2.3xl0'7, 2.2 / 10'7, 2.1 - Hr7. 2.0xl0'7, 1.9 / 10'7, 1.8xl0'7, 1.7 / 10'7, 1.6xl0'7, 1.5 / 10'7, 1.4 / 10'7, 1.3 / 10-7, 1.2xl0‘7, l.lxlO'7, l. OxlO’7, 9.0xl0'8, 8.9 / IO'8, 8.8 / 10"8, 8.7 / 10'8, 8.6x]0’8, 8.5xlO’8, 8.4 / 10'8, 8.3xlO's, 8.2 / 10'8, 8.1xlO'8, 8.0 / 10'8, 7.9 / 10’8, 7.8x IO'8, 7.7xl0'8, 7.6 1 O’8. 7.5 / 10'8, 7.4 / 10'8, 7.3 / 10'8, 7.2 / 10'8, 7.1 / 10'8, 7.0 / 10-8, 6.9xl0‘8, 6.8x IO'8, 6.7xl0'8, 6.6 / 10'8, 6.5 / 10'8, 6.4 1(0. 6.3 / 10-8, 6.2 / IO"8, 6 / lxlO-8, 6.0xl0’s, 5.9X10’8, 5.8X10"8, 5.7 / 10'8, 5.6 / 10'8, 5.5xlO'8, 5.4x]0’8, 5.3xl0‘8, 5.2xl0‘s, 5.1 / 10'8, 5.0X10"8, 4.9xlCr8?4.8 / I0'8, 4.7 / I0'8, 4.6x]0’8, 4.5xl0’8, 4.4xl0‘s, 4.3 / 10'8, or4.2xl0’8M, 4.1 / 10'8, 4.0X10'8, 3.9 / 10'8, 3.8 - OO’8, 3.7 / 10’8, 3.6 / IO'8. 3.5 / 10'8, 3.4xl0'8, 3.3 / 10'8, 3.2 / 10'8, 3.1 / 10-8, 3.0xl0‘8, 2.9xl0‘8, 2.8xl0‘8, 2.7xl0’8, 2.6 / 10'8, 2.5 / 10"8, 2.4 / 10'8, 2.3x]0’8, 2.2x l0’s, 2.1xl0~s, 2.0xl0~s, 1.9 / 10"8, 1.8xlO"8, 1.7zl0’8, 1.6 / 10’8, 1.5xlO'8, 1.4xl0'8, 1.3x1 O’8. 1.2 / 10'8, 1.1 x IO'8, l. OxlO’8, 9.0xlCr9, 8.9 / 10’9, 8.8 / 10-9, 8.7xl0‘9, 8.6xl0‘9, 8.5xl0’9, 8.4xl0'9, 8.3xl0'9, 8.2 Hr9. 8.1 / 10-9, 8.0X10’9, 7.9xl0‘9, 7.8xl0~9, 7.7xl0’9, 7.6xl0"9, 7.5xl0'9, 7.4xl0'9, 7.3x]0’9, 7.2x]0’9, 7.1xl0‘9, 7.0xl0‘9, 6.9 / 10'9, 6.8xlCr96.7xlCr9?6.6 / I0'9, 6.5 / I0'9, 6.4x]0’9, 6.3xl0’9, 6.2xl0‘9, 6.1X10'9, 6.0X10'9, 5.9'xlO-9, 5.8 / 10'9, 5.7 / 1Q-9, 5.6 / IO'9. 5.5 / 10'9, 5.4 / IO’9. 5.3 / 10'9, 5.2xl0'9, 5.1 / 10'9, 5.0 / 10'9, 4.9X10'9, 4.8xl0‘9, 4.7xl0‘9, 4.6xW9, 4.5 / 10’9, 4.4 / 10'9, 4.3 / 10"9, or4.2x]0’9, 4.1 x l0‘9, 4,( Hr93.9 / 10"9, 3.8xl0“9, 3.7xl0’9, 3.6z]0’9, 3. xl0’9, 3.4 / 10"9, 3.3x]0'9, 3.2xl0’9, 3.1xl0’9, 3.0 / IO'9, 2.9x IO'9, 2.8 / W9, 2.7 / lCr9, 2.6xl0“9, 2.5 x H9. 2.4xl0‘9, 2.3xl0’9, 2.2xl0’9, 2. lx IO'9, 2.0xl0'9, 1.9 / IO'9, and 1.8 / IO'9M) in a bivalent format (i.e., a construct comprising two anti-Co!2 ISVDs), as measured by SPR. In certain embodiments, the ISVD specifically binds to Col2 with a KD of between 6.0 / IO"8and 1.8X10'9M (e.g., 6.0 / 10'8, 5.9 / 10’8, 5.8 / IO’8, 5.7xl(y8, 5.6xl0'8, 5.5x W8, 5.4xl0'8, 5.3x10'8, 5.2x IO'8, 5.1 x IO'8, 5.0x IO'8, 4.9 / IO'8, 4.8 IO'8, 4.7x IO'8, 4.6x IO'8, 4.5x IO'8, 4.4x IO'8, 4.3xl0'8, 4.2 / 10'8, 4.1 X10'8, 4.0xl0'8, 3.9 / 10'8, 3.8xlO's, 3.7X10"8, 3.6xl0'8, 3.5 / 10'8, 3.4 / I0'8, 3.3xlO’8, 3.2xl0'8, 3.1xlO'8, 3.0 / 10'8, 2.9 / 10'8, 2.8 / 10'8, 2.7 / lCr8, 2.6 / 10'8, 2.5 / 10'8, 2.4xl0'8, 2.3xl0'8, 2.2xl0'8, 2.1xl0'8, 2.0xl0'8, 1.9> IO'8, 1.8 / 10'8, 1.7 / 10'8, 1.6 / 10'8, 1.5xlO'8, 1.4 / 10'8, 1.3xlO'8, 1.2.x IO'8, l.lxlO'8, 1.0 / IO'8, 9.0 / 10'9, 8.9 / 10'9,74 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO8.8xl0'9, 8.7xl0'9, 8.6xl0'9, 8.5 / 11% 8.4xl0‘9, 8.3xl0’9, 8.2x 10‘9, 8.1xl0’9, 8.0 / 10'9, 7.9X10’9, 7.8xl0'9, 7.7xi0’9, 7.6 / 10’9, 7.5xl0~9, 7.4xl0~9, 7.3 / 10"9, 7.2xl0“9, 7.1xl0’9, 7.0xI0“9, 6.9x]0'9, 6.8xl0’9, 6.7 / 10’9, 6.6 / 10'9, 6.5 / 10'9, 6.4 / 10"9, 6.3xl0’9, 6.2 / 10"9, 6.1X10’9, 6.0xl0-9, 5.9xl0'9, 5.8X10'9, 5.7xl0'9, 5.6xl0'9, 5.5 / 10'9, 5.4 / 10’9, 5.3 / 10’9, 5.2x 10‘9, 5.1 x 10‘9, 5. Ox 10‘9, 4.9x IO’9, 4.8x 10'9, 4.7 / IO'9, 4.6 < IO'9, 4,5 1 (r9. 4.4 / I (% 4.3xl0‘9, or4.2xl0"9, 4.1xl0’9, 4 0 IO'9. 3.9 / IO’9, 3.8x IO’9, 3.7 / 10‘9, 3.6 / 10‘9, 3.5 / 10"9, 3.4xl0‘9, 3.3xl0'9, 3.2xl0"93.1xlCr9, 3.0 / I0'9, 2.9 / I0'9, 2.8x]0’9, 2.7xl0’9, 2.6xl0‘9, 2.5 x IO'9, 2.4 / 1 O'9. 2.3 x IO'9, 2.2 / 10’9, 2.1 x 10'9, 2.0x 10'9, 1.9 / 10'9, and i. S 10'9M) in a bivalent format (i.e., a construct comprising two anti-Co!2 ISVDs).

[0152] In certain embodiments, the ISVD is cross-reactive with human Col2 and Col2 of at least one other mammalian species. In certain embodiments, the at least one other mammalian species is a rodent or non-human primate. In certain embodiments, the rodent is a rat. In certain embodiments, the non-human primate is a rhesus macaque.

[0153] In certain embodiments, the ISVD has a melting temperature of at least 50°C (e.g., at least 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C, 69°C, 70°C, 71°C, 72°C, 73°C, 74°C, 75°C, 76°C, 77°C, 78°C, 79°C, 80°C, 81 °C, 82°C, 83°C, 84°C, 85°C, or more).

[0154] In certain embodiments, tire ISVD competes for binding with a reference anti-Co!2 antibody to an epitope of Col2. In certain embodiments, the anti-Col2 reference antibody comprises an amino acid sequence having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to any one of SEQ ID NOs: 356-477 and 6928-6951. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 356. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 357. In certain embodiments, the ISVD competes for binding ■with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 358. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 359. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 360. In certain embodiments, the ISVD competes for binding with an anti-Col275 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOreference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 361. In certain embodiments, tire ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 362. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 363. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 364. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 365. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 366. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 367. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 368. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 369. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 370. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 371. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 372. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 373. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 374. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 375. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an 76 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOepitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 376. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 377. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 378. In certain embodiments, the ISVD competes for binding -with an anti-CoI2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 379. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 380. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 381. In certain embodiments, the ISVD competes for binding ■with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 382. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 383. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 384. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 385. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 386. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 387. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 388. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 389. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 390. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the 77 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOreference antibody comprises an amino acid sequence of SEQ ID NO: 391. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of CoI2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 392. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 393. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 394. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 395. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 396. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 397. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 398. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 399. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 400. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, vrherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 401. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 402. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 403. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 404. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 405. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody 78 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOcomprises an amino acid sequence of SEQ ID NO: 406. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 407. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 408. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 409. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 410. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 411. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 412. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wdrerein the reference antibody comprises an amino acid sequence of SEQ ID NO: 413. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 414. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 415. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 416. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 417. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 418. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 419. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 420. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino 79 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOacid sequence of SEQ ID NO: 421. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 422. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 423. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 424. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 425. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 426. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 427. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 428. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 429. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 430. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 431. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of CoI2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 432. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Co! 2. wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 433. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 434. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 435. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ 80 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOID NO: 436. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 437. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 438. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 439. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 440. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 441. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 442. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 443. In certain embodiments, the ISVD competes for binding w ith an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 444. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 445. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 446. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 447. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 448. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 449. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 450. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 451. In certain 81 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOembodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 452. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 453. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 454. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 455. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 456. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 457. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 458. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 459. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 460. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 461. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 462. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 463. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 464. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 465. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 466. In certain embodiments, the ISVD 82 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOcompetes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 467. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 468. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 469. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 470. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 471. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 472. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 473. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 474. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 475. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 476. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 477. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6928. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6929. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6930. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6931. In certain embodiments, the ISVD competes for binding 83 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOwith an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6932. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6933. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6934. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6935. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6936. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6937. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6938. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6939. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6940. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6941. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6942. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6943. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6944. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6945. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, w herein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6946. In certain embodiments, the ISVD competes for binding with an anti-Co!284 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOreference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6947. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6948. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6949. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6950. In certain embodiments, the ISVD competes for binding with an anti-Col2 reference antibody to an epitope of Col2, wherein the reference antibody comprises an amino acid sequence of SEQ ID NO: 6951. In certain embodiments, the ISVD competes for binding with an anti-Co!2 reference antibody to an epitope of Col2, wherein the reference antibody comprises any one of the anti-Col2 avimers described in Hulme et al. J. Ortho. Res.36(4):1238-47 (2017) (e.g., anti-Col2 avimer M26).

[0155] In certain embodiments, the ISVD further comprises an Fc region.BRIEF DESCRIPTION OF THE DRAWINGS

[0156] FIG. 1 shows an illustration of a representative bispecific polypeptide of disclosure which includes an anti-IL-1β VHH connected to an anti-Col2 VHH via a peptide linker. Each VHH domain has a molecular weight of approximately 12-15 kDa. When combined with the linker, the total molecular weight of the bi specific polypeptide is approximately 30-36 kDa.

[0157] FIG. 2 is a series of plots showing surface plasmon resonance (SPR) data with resonance units (RU) in the y -axis, demonstrating binding of seven different anti-IL-1β VHH clones to human IL-1β, including clones 162, 163, 164, 165, 1140, 1141, and 1142.

[0158] FIG. 3 is a series of plots showing SPR data with resonance units (RU) in the y -axis, demonstrating binding of seven different anti-IL-1β VHH clones to rhesus macaque IL-1β, including clones 162, 163, 164, 165, 1140, 1141, and 1142.

[0159] FIG. 4 is a plot showing a saturation curve for binding of human IL-1β to immobilized human IL-1 receptor 1 (IL-1R1), as measured by SPR.

[0160] FIG. 5 is a series of plots showing inhibition curves and IC50 values for seven anti-IL-1β VHH clones, including 162, 163, 164, 165, 1140, 1141, and 1142, blocking binding of human IL-1β to human IL-1R1.

[0161] FIG. 6 is a series of plots showing inhibition curves for five anti-IL-1β VHH clones, including 162, 163, 165, 1140, and 1142, blocking binding of human IL-1β to rat IL-1R1.85 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO

[0162] FIG. 7 is a plot showing binding of five anti-Col2 VHH clones, including Cl 7, C48, C76, C95, and C99, to Col2, and a negative control VHH (BCII10), as measured by an ELISA titration assay.|0163] FIG. 8 is a series of plots showing binding of anti-hCol2 Fc-VHH clones to immobilized human Col2 (hCol2) and hCol2 cyanogen bromide cleaved peptide 10 (hCol2-CB10), as determined by an ELISA assay,

[0164] FIG. 9 shows the parental and humanized variant (“var”) sequences of 162. The CDR1, CDR2 and CDR3 sequences of the humanized variant sequences were unmodified.

[0165] FIG. 10 shows Biacore sensograms recorded during the affinity determination on IL-1β of anti-IL-1β VHH clones I62 h1a85 (upper left), I62 h1a86 (upper right), I62 h1a87 (lower left), and I62 a88 (lower right). X-axis: time (s), Y-axis; response units (RU).DETAILED DESCRIPTIONDefinitions

[0166] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. Generally, nomenclatures utilized in connection with, and techniques of immunology, molecular biology, and protein chemistry described herein are those well- known and commonly used in the art. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0167] As used herein, singular forms “a,” "‘and,” and “the” include plural referents unless the context clearly indicates otherwise. Thus, e.g., reference to “a polypeptide” includes a plurality of antibodies and reference to “a polypeptide” includes multiple antibodies, and so forth,

[0168] As used herein, all numerical values or numerical ranges include whole integers within or encompassing such ranges and fractions of the values or the integers within or encompassing ranges unless tire context clearly indicates otherwise. Thus, e.g., reference to a range of 90-100%, includes 91%, 92%, 93%, 94%, 95%, 96%, 97%, etc,, as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth. In another example, reference to a range of 1-5,000 fold includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,86 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO11, 12, 13, 14, 15, 16, 17, 18, 19, 20-fold, etc., as well as 1.1, 1.2, 1.3, 1.4, 1.5-fold, efc., 2.1, 2.2, 2.3, 2.4, 2.5-fold, etc., and so forth.

[0169] “About’’ a number, as used herein, refers to range including the number and ranging from 10% below that number to 10% above that number. “About” a range refers to 10% below the lower limit of the range, spanning to 10% above the upper limit of the range.

[0170] The terms “antigen-binding portion,” “antigen-binding fragment,” and “antigenbinding domain,” are used interchangeably herein to refer to one or more fragments of a polypeptide (e.g., a VHH) that retain the ability to specifically bind to a target antigen. Nonlimiting examples of polypeptide fragments included within such terms include, but are not limited to antigen-binding fragments of a VHH domain.

[0171] As used herein, the term “bispecific” refers to a property of a polypeptide, such as a polypeptide (e.g., a VHH) having binding specificities for at least two different epitopes (e.g., an epitope of IL-1β and an epitope of Col2). In certain embodiments, bispecific polypeptides bind to two different epitopes of a single antigen. Other such polypeptides, in certain embodiments, combine a first antigen binding site with a binding site for a second antigen.

[0172] The term “CDR” denotes a complementarity determining region as defined by at least one manner of identification to one of skill in the art. In certain embodiments, CDRs can be defined in accordance with any of the Chothia numbering schemes, the Kabat numbering scheme, a combination of Kabat and Chothia, the IMGT definition, the AbM definition, and / or the Contact definition. Under the Kabat numbering scheme, in certain embodiments, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3); and the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3), Under the Chothia numbering scheme, in certain embodiments, the CDR amino acids in the VH are numbered 26-32 (HCDRl), 52-56 (HCDR2), and 95-102 (HCDR3); and the CDR amino acid residues in the VL are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3). In a combined Kabat and Chothia numbering scheme, in certain embodiments, the CDRs correspond to the amino acid residues that are part of a Kabat CDR, a Chothia CDR, or both. For instance, in certain embodiments, the CDRs correspond to amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in a VH, e.g., a mammalian VH, e.g., a human VH; and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3) in a VL, e.g., a mammalian VL, e.g., a human VL. A VHH comprises three heavy chain CDRs, designated CDR1, A CDR2, and CDR3 (alternatively87 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOHCDR1, HCDR2, and HCDR3; Hl-CDR, H2-CDR, and H3-CDR; or CDR-H1, CDR-H2, and CDR-H3).

[0173] As used herein, the phrase “competes for binding” or the like, when referring to two antibodies or antigen-binding fragments thereof, means that the first antibody or antigenbinding fragment thereof blocks, inhibits, or reduces binding of a second antibody or antigen¬ binding fragment thereof to a target epitope by any amount (e.g., at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more). Methods for measuring competitive binding between two antibodies to a target epitope are well-known in the art.

[0174] The term “effective amount” as used herein, refers to that amount of a therapeutic agent (e.g., a polypeptide disclosed herein) or a composition comprising the same as described herein, that is sufficient to induce a disclosed effect, e.g., to effect treatment, prognosis, or diagnosis of a disease, as described herein, when administered to a subject. Therapeutically effective amounts of therapeutic agents provided herein, when used alone or in combination, will vary depending upon the relative activity of the disclosed agents (e.g., in treating, reducing, or ameliorating a disease or disorder described herein) and depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration, and the like, which, in some cases, are readily determined by one of ordinary skill in the art.

[0175] As used herein, the term “epitope” refers to a site on a target molecule (e.g., an antigen, such as a protein, nucleic acid, carbohydrate, or lipid) to which an antigen-binding molecule (e.g., a VHH-containing polypeptide) binds. Epitopes often include a chemically active surface grouping of molecules such as amino acids, polypeptides or sugar side chains and have specific three-dimensional structural characteristics as well as specific charge characteristics. Epitopes can be formed both from contiguous and / or juxtaposed noncontiguous residues (e.g., amino acids, nucleotides, sugars, and lipid moiety) of the target molecule. Epitopes formed from contiguous residues (e.g., amino acids, nucleotides, sugars, and lipid moiety) typically are retained on exposure to denaturing solvents whereas epitopes formed by tertiary folding typically are lost on treatment with denaturing solvents. An epitope may include but is not limited to at least 3, at least 5 or 8-10 residues (e.g., amino acid residues). In certain embodiments, an epitope is less than 20 residues (e.g., amino acid residues) in length, less than 15 residues or less than 12 residues. Two antibodies may bind the same epitope within an antigen if they exhibit competitive binding for the antigen, in certain embodiments, an epitope can be identified by a certain minimal distance to a CDR 88 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOresidue on the antigen-binding molecule. In certain embodiments, an epitope can be identified by the above distance, and further limited to those residues involved in a bond (e.g., a hydrogen bond) between a residue of the antigen-binding molecule and an antigen residue. An epitope can be identified by various scans as well, e.g., an alanine or arginine scan can indicate one or more residues that the antigen-binding molecule can interact with. Unless explicitly denoted, a set of residues as an epitope does not exclude other residues from being part of the epitope for a particular antigen -binding molecule. Rather, the presence of such a set designates a minimal series (or set of species) of epitopes. Thus, in certain embodiments, a set of residues identified as an epitope designates a minimal epitope of relevance for the antigen, rather than an exclusive list of residues for an epitope on an antigen.|0176] As used herein, the term ‘"host cell” refers to a cell in which a vector can be propagated and its nucleic acid sequence expressed. For example, a disclosed VHH- containing polypeptide can be expressed in a host cell. The cell may be prokaryotic or eukaryotic. The term also includes any progeny of the host cell. It is understood that all progeny may not be identical to the parental cell since there may be mutations that occur during replication. However, such progeny are included when the term “host cell” is used.

[0177] As used herein, the term “IL-1β-mediated inflammatory disease or disorder” refers to any inflammatory disease or condition in which IL- 1 P signaling is associated with or mediates the underlying disease etiology. For example, an IL-i -mediated inflammatory disease or disorder may be an inflammatory disease or disorder associated with aberrant (e.g., increased relative to a healthy control) IL- 1 P expression and / or activity. Non-limiting examples of an IL-1β-mediated inflammatory disease or disorders include osteoarthritis, refractory gout, and noninfectious uveitis.

[0178] As used herein, the term “immunoglobulin single variable domain” or “ISVD” refers to a polypeptide comprising a variable domain of an immunoglobulin or that, under suitable conditions (e.g., physiological conditions), is capable of forming an immunoglobulin variable domain, such as a VHH.

[0179] The terms “inhibition” or “inhibit” refer to a decrease, cessation, or suppression of any phenotypic characteristic or to the decrease, cessation, or suppression in tlie incidence, degree, or likelihood of that characteristic. For example, IL- Ip binding to its natural ligand Interleukin 1 Receptor Type 1 (IL-1R1) can mediate downstream signaling pathways, and a VHH-containing polypeptide that specifically or preferentially binds to IL- 1 P may inhibit IL-1β binding to IL-1R1 or inhibit IL- 1R1 -mediated downstream signaling pathways following binding between IL- Ip and IL-1R1. A VHH-containing polypeptide that inhibits IL- Ip 89 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOsignaling and / or ligand binding can be referred to as an “antagonist,” a “blocking,” or “neutralizing” antibody. To “reduce” or “inhibit” is to decrease, reduce, suppress, or arrest an activity, function, amount, abundance, or rate of increase as compared to a reference. In certain embodiments, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 10% or greater. In certain embodiments, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 50% or greater. In certain embodiments, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 75%, 85%, 90%, 95%, or greater. In certain embodiments, the amount noted above is inhibited or decreased over a period of time, relative to a control over the same period of time. In certain embodiments, a neutralizing antibody binds to an antigen and reduces its biological activity by at least about 20%, 40%, 60%, 80%, 85% 90%, 95%, 99% or more.

[0180] lire term “KD”, as used herein, refers to the equilibrium dissociation constant of an antigen-binding molecule / antigen interaction or a ligand / receptor interaction. When the term “KD” is used herein, it includes KD and Ko-apparent. Tire term “ka” or “kon”, as used herein, refers to the association rate (or “on-rate”) at which one molecule binds to the second to form a complex (e.g., an antigen-binding molecule binding to an antigen), typically reflected as moles per second (M⁻¹s⁻¹ or 1 / Ms), The term “kd” or “kotr”, as used herein, refers to the dissociation rate (or “off-rate”) at which one molecule dissociates from its binding partner (e.g., ligand) in a complex (e.g, an antigen- binding molecule dissociating from its bound antigen), typically reflected as per second (s’1or 1 / s), KD is the ratio of kd to ka (kd / ka; also represented as koff / kon). In certain embodiments, the KD of the antigen -binding molecule is measured by surface plasmon resonance (SPR).

[0181] As used herein, “percent (%) amino acid sequence identity” and “homology” with respect to a peptide, polypeptide, or antibody sequence are defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not consi dering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGN (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.90 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO

[0182] An amino acid substitution may include but is not limited to the replacement of one amino acid in a polypeptide with another amino acid. Exemplary substitutions are shown in Table 1. Amino acid substitutions may be introduced into an polypeptide of interest and the products screened for a desired activity, e.g., retained / improved antigen binding, decreased immunogenicity, etc.Table 1: Amino Acid SubstitutionsOriginal Residue Exemplary SubstitutionsAla (A) Val; Leu; IleArg (R) Lys; Gin; AsnAsn (N) Gin; His; Asp, Lys; ArgAsp (D) Glu; AsnCys (C) Ser; AlaGin (Q) Asn; GluGlu (E) Asp; GinGly (G) AlaHis (H) Asn; Gln; Lys; ArgIle (I) Leu; Val; Met; Ala; PheLeu (L) Ile; Val; Met; Ala; PheLys (K) Arg; Gin; AsnMet (M) Leu; Phe; IlePhe (F) Trp; Leu; Val; Ile; Ala; TyrPro (P) AlaSer (S) ThrThr (T) Vai; SerTrp (W) Tyr; PheTyr (Y) Trp; Phe; Thr; SerVal (V) Ile; Leu; Met; Phe; Ala

[0183] Amino acids may be grouped according to common side-chain properties:(1) hydrophobic: Met, Ala, Vai, Leu, He;(2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gin;(3) acidic: Asp, Glu;(4) basic: His, Lys, Arg;91 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO(5) residues that influence chain orientation: Gly, Pro;(6) aromatic: Trp, Tyr, Phe.

[0184] Non-conservative substitutions will entail exchanging a member of one of these classes for another class.

[0185] As used herein, the term “pharmaceutically acceptable” refers to those compounds, materials, compositions and / or dosage forms, which are suitable for contact with the tissues of a subject, such as a mammal (e.g., a human) without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit / risk ratio.

[0186] The terms “pharmaceutical formulation” and “pharmaceutical composition” are used interchangeably and refer to a preparation which is in such form as to permit the biological activity of the active ingredient(s) to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. Such formulations may be sterile.

[0187] As used herein, the term “polypeptide” refers to a polymer of amino acid residues, and are not limited to a minimum length. Such polymers of amino acid residues may contain natural or non-natural amino acid residues, and include, but are not limited to, peptides, oligopeptides, and full-length forms and fragments of natural polypeptides. The terms also include post-translational modifications of the polypeptide, e.g., glycosylation, sialylation, acetylation, phosphorylation, and the like. Furthermore, for purposes of the present disclosure, a “polypeptide” can include modifications, such as deletions, additions, and substitutions (generally conservative in nature), to the native sequence, as long as tire it maintains the desired activity. Within the context of the present disclosure the term polypeptide may refer to a VHH-containing polypeptide. In certain embodiments, a polypeptide refers to a bispecific molecule comprising a first VHH that specifically binds to IL- 1 [3 and at least one second VHH that specifically binds to CoI2, wherein the first and at least one second VHH are optionally connected by a peptide linker.

[0188] The terms “recipient,” “individual,” “subject,” “host,” and “patient,” are used interchangeably herein and refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired, particularly humans. “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and laboratory, zoo, sports, or pet animals, such as rats, monkeys, etc. In certain embodiments, the mammal is a human. None of the terms require the supervision of a medical professional.

[0189] The term “specifically binds” to an antigen or epitope is a term that is well-understood in the art, and methods to determine such specific binding are also well-known in 92 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOthe art. A molecule is said to exhibit “specific binding” or “preferential binding” if it reacts or associates more frequently, more rapidly, with greater duration, and / or with greater affinity with a particular cell or substance than it does with alternative cells or substances. For example, a VHH-containing polypeptide (e.g., a VHH-containing polypeptide disclosed herein) “specifically binds” or “preferentially binds” to a target if it binds with greater affinity, avidity, more readily, and / or with greater duration than it binds to other substances. For example, a VHH-containing polypeptide that specifically or preferentially binds to an IL-1 epitope is a VHH-containing polypeptide that binds this epitope with greater affinity, avidity, more readily, and / or with greater duration than it binds to other IL- 1 p epitopes or non-IL-1β epitopes. It is also understood by reading this definition that, e.g., a VHH-containing polypeptide that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to an ortholog of the same target in another species (e.g., another mammalian species). For example, a VHH-containing polypeptide that specifically or preferentially binds to human IL-1β may specifically or preferentially bind to IL-1β of a rodent (e.g., rat) or non-human primate (e.g., rhesus macaque). As such, “specific binding” or “preferential binding” does not necessarily require (although it can include) exclusive binding. Non-exclusive binding can also be referred to as “cross-reactive” binding. For instance, an VHH-containing polypeptide that is cross-reactive with human and rodent IL- 1 is a VHH-containing polypeptide that can bind to both human and rodent IL- 1 p. Generally, but not necessarily, reference to binding means preferential binding. “Specificity” refers to the ability of a binding protein to selectively bind an antigen.

[0190] The term “therapeutically effective amount” generally refers to an amount of a disclosed polypeptide or a drug effective to “treat” a disease or disorder in a subject or mammal. In certain embodiments, a composition described herein is administered to a subject in an amount that is effective for producing some desired therapeutic effect by inhibiting a disease or disorder as described herein at a reasonable benefit / risk ratio applicable to any medical treatment, A therapeutically effective amount is an amount that achieves at least partially a desired therapeutic or prophylactic effect in an organ or tissue. The amount of a polypeptide necessary to bring about prevention and / or therapeutic treatment of a disease or disorder is not fixed per se. In certain embodiments, the amount of the polypeptide administered vanes with the type of disease, extensiveness of the disease, and size of the mammal suffering from the disease or disorder. When used in conjunction with therapeutic methods involving administration of a therapeutic agent after the subject presents symptoms93 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOof a disease or disorder, the term "‘therapeutically effective” means that, after treatment, one or more signs or symptoms of the disease or disorder is ameliorated or eliminated.

[0191] An effective response resulting from administration of a polypeptide of the present disclosure is achieved when the subject experiences partial or total alleviation or reduction of signs or symptoms of illness and, in the case of the treatment of a disease, specifically includes, without limitation, amelioration of symptoms, prolongation of progression, cure, remission, prolongation of survival, or other objective responses. In certain embodiments, the expected progression-free survival times are measured in months to years, depending on prognostic factors including the number of relapses, stage of disease, and other factors.Prolonging survival includes without limitation times of at least 1 month (mo.), about at least 2 mos., about at least 3 mos., about at least 4 mos., about at least 6 mos., about at least 1 year, about at least 2 years, about at least 3 years, etc. Overall survival is also measured, e.g., in months to years. Alternatively, an effective response, in certain embodiments, is that a subject’s symptoms remain static. Further indications of treatment of indications are described in more detail below.

[0192] In certain embodiments, administration of a therapeutic agent in a prophylactic method occurs prior to the manifestation of symptoms of an undesired disease or disorder, such that the disease or disorder is prevented or, alternatively, delayed in its progression. Thus, when used in conjunction with prophylactic methods, the term “therapeutically effective” means that, after treatment, a smaller number of subjects (on average) develop the undesired disease or disorder or progress in severity of symptoms.

[0193] As used herein, the terms “treatment,” “treating,” and the like, in some cases, refer to administering an agent, or carrying out a procedure, for the purposes of obtaining an effect. Tire effect may be prophy lactic in terms of completely or partially preventing a disease or symptom thereof and / or is therapeutic in terms of effecting a partial or complete cure for a disease and / or symptoms of the disease. “Treatment,” as used herein, includes treatment of a disease or disorder in a mammal, particularly in a human, and includes: (a) preventing the disease or a symptom of a disease from occurring in a subject which is predisposed to the disease but has not yet been diagnosed as having it (e.g., including diseases that is associated with or caused by a primary disease); (b) inhibiting the disease, i. e., arresting its development; and (c) relieving the disease, z.e., causing regression of the disease. Tire term treating includes any indicia of success in the treatment or amelioration or prevention of a disease or disorder, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the disease condition more tolerable to the 94 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOpatient; slowing in the rate of degeneration or decline; or making the final point of degeneration less debilitating, lire treatment or amelioration of symptoms is based on one or more objective or subjective parameters, including the results of an examination by a physician. Accordingly, tlie term “treating” includes the administration of the agents of the present disclosure to prevent or delay, to alleviate, or to arrest or inhibit development of the symptoms or conditions associated with diseases. Tire term “therapeutic effect” refers to the reduction, elimination, or prevention of the disease, symptoms of the disease, or side effects of the disease in the subject. A subject is “treated” for a disease or disorder if, after receiving a therapeutic amount of a polypeptide of the present disclosure, the patient shows observable and / or measurable change in a parameter or symptom of the disease or disorder,|0194] As used herein, the term “vector” or “expression vector” includes a nucleic acid vector, e.g, a DNA vector, such as a plasmid, an RNA vector, virus, or other suitable replicon (e.g., viral vector). A variety of vectors have been developed for the delivery of polynucleotides encoding exogenous proteins into a prokaryotic or eukaryotic cell. Examples of such expression vectors are generally well-known. Expression vectors suitable for use with the compositions and methods described herein contain a polynucleotide sequence as well as, e.g., additional sequence elements used for the expression of proteins and / or the integration of these polynucleotide sequences into the genome of a mammalian cell. Certain vectors that can be used for the expression of the bispecific polypeptide as described herein include plasmids that contain regulatory sequences, such as promoter and enhancer regions, which direct gene transcription. Other useful vectors for expression of the bispecific polypeptide disclosed herein contain polynucleotide sequences that enhance the rate of translation of these genes or improve the stability or nuclear export of the mRNA that results from gene transcription. These sequence elements include, e.g., 5' and 3' untranslated regions, an IRES, and polyadenylation signal site in order to direct efficient transcription of the gene carried on the expression vector. The expression vectors suitable for use with the compositions and methods described herein may also contain a polynucleotide encoding a marker for selection of cells that contain such a vector. Examples of a suitable marker are genes that encode resistance to antibiotics, such as ampicillin, chloramphenicol, kanamycin, nourseothricin, or zeocin..

[0195] The term “VHH” or “VHH domain,” as used herein, refers to the antigen -binding domain of a single domain antibody (sdAb). In certain embodiments, a VHH comprises three CDRs and four framework regions, designated FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. In certain embodiments, a VHH may be truncated at the N-terminus or C-terminus such 95 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOthat it comprises only a partial FR1 and / or FR4, or lacks one or both of those framework regions, so long as the VHH domain substantially maintains antigen binding and specificity. In certain embodiments, an antigen-binding domain of a VHH-containing polypeptide comprises three CDRs of a VHH domain. Thus, in certain embodiments, an antigen binding domain of a VHH-containing polypeptide comprises a VHH domain comprising CDR1-FR2-CDR2-FR3-CDR3, and any portions of FR1 and / or FR4 required to maintain binding to antigen.Overview

[0196] The present disclosure provides bispecific polypeptides comprising a first binding portion that specifically binds to Interleukin 1 Beta (IL- Ip) and a second binding portion that specifically binds to Type II Collagen (Col2). The first and second binding portions are, in certain embodiments, physically connected via a peptide linker as described herein. Such polypeptides are useful in selectively producing inhibition and / or sequestration of IL- ip at a target cell, tissue, or organ that expresses Col2. Also disclosed herein are pharmaceutical compositions containing a bispecific polypeptide of the disclosure and one or more pharmaceutically acceptable carriers, diluents, or excipients. The present disclosure further provides methods of using the disclosed polypeptides or compositions comprising the same for the treatment of a disease or disorder (e.g,, an inflammatory disease or disorder, such as an IL-1 p-mediated inflammatory’ disease or disorder, e.g., osteoarthritis, refractory gout, and noninfectious uveitis), such methods comprising administering the polypeptides or tire compositions to a subject in need thereof by any acceptable route (e.g., by way of intra¬ articular administration).

[0197] In certain embodiments, a bispecific polypeptide of the disclosure comprises two or more (e.g., 2, 3, 4, or more) immunoglobulin single variable domains (ISVDs), such as VHH domains (see FIG. 1). In certain embodiments, the bispecific polypeptides of the disclosure comprise three ISVDs. ISVDs can be obtained by genetic engineering or immunization to yield a small binding protein having high affinity for a target antigen, resulting in a low' molecular weight antibody-derived protein known as a “camelid antibody” or a “VHH.” VHH domains have a number of unique structural and functional properties which render them highly advantageous for use as functional antigen-binding domains or proteins. In particular, and without being limited thereto, VHH domains can function as a single, relatively small, functional antigen-binding structural unit, domain, or protein. This distinguishes the VHH domains from the VH and VL domains of conventional 4-chain 96 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOantibodies which by themselves are generally not suited for practical application as single antigen-binding proteins or domains, but need to be combined in some form or another to provide a functional antigen-binding unit.|0198] Moreover, a VHH has a molecular weight approximately one-tenth that of a human immunoglobulin molecule, and the protein has a physical diameter of only a few nanometers. One consequence of the small size is the ability of the VHH to bind to antigenic sites that are functionally invisible to larger antibody proteins, such that the VHHs are useful as agents to target antigens that are otherwise cryptic using classical immunological techniques, and thus are of use as therapeutic agents. Yet another consequence of small size is that a VHH can be a particularly potent inhibitor of target proteins as a result of binding to a specific site in a groove or narrow cleft of a target protein, and hence can serve in a capacity that more closely resembles the function of a classical low molecular weight drug than that of a classical antibody. Further still, the small size of VHH molecules can allow them, in certain embodiments, to exhibit high tissue penetration, which may be particularly advantageous for localized and / or systemic delivery of VHH-containing molecules.Interleukin 1 Beta

[0199] IL- ip is a pyrogenic cytokine belonging to the interleukin 1 family of cytokines. Production of the IL- 1 p precursor is mediated by activated macrophages, monocytes, and specialized dendritic cells, followed by proteolytic cleavage of the precursor by caspase 1 to produce the mature IL-i protein. IL- i signaling through its cognate receptor Interleukin 1 Receptor Type 1 (IL-1R1) mediates the inflammatory response by inducing prostaglandin synthesis, neutrophil activation, T cell activation, B cell activation, antibody production, and cytokine production, IL-lp signaling is also involved in cell proliferation, differentiation, and apoptosis.|0200] The amino acid sequence of the human IL-lp precursor protein is provided in SEQ ID NO: 1 (UniProt Ref. No. P01584).MAEVPELASEMMAYYSGNEDDLFFEADGPKQMKCSFQDLDLCPLDGGIQLRISDHH YSKGFRQAASVVVAMDKLRKMLVPCPQTFQENDLSTFFPFIFEEEPIFFDTWDNEAY VHDAPVRSLNCTLRDSQQKSLVMSGPYELKALHLQGQDMEQQVVFSMSFVQGEES NDKIPVALGLKEKNLYLSCVLKDDKPTLQLESVDPKNYPKKKMEKRFVFNKIEINNK LEFESAQFPNWYISTSQAENMPVFLGGTKGGQDITDFTMQFVSS(SEQ ID NO: 1)97 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO

[0201] The amino acid sequence of the mature human IL- ip protein is provided in SEQ ID NO: 2 (UniProt Ref. No. P01584).APVRSLNCTLRDSQQKSLVMSGPYELKALHLQGQDMEQQVVFSMSFVQGEESNDKI PVALGLKEKNLYLSCVL DDKPTLQLESVDPKNTTKKKMEKRFVFNKIEINNKLEFE SAQFPNWYISTSQAENMPVFLGGTKGGQDITDFTMQFVSS(SEQ ID NO: 2)

[0202] The amino acid of the sequence of the rhesus macaque (Macaco mulatto) IL- i precursor protein is provided in SEQ ID NO: 3 (NCBI Ref. Seq. NP 001036221.1).MAEVPELASEMMAYYSGNEDDLFFDVDGPKQMKCSFQDLDLCPLGGGIQLQISHEH YNEGFRQAVSVVVAMEKLRKMLVPCPQIFQDNDLSTLIPFIFEEEPVFLDTRNNDAC VHDAPVRSLHCTLRDAQLKSLVMSGPYELKALHLQGQDLEQQVVFSMSFVQGEESN DKIPVALGLKAKNLYLSCVLKDDKPTLQLESVDPKNYPKKKMEKRFVFNKIEINNKL EFESAQFPNWYISTSQAENMPVFLGGTRGGQDITDFTMQFVSS(SEQ ID NO: 3)

[0203] The amino acid sequence of the mature rhesus macaque IL- 1 P is provided in SEQ ID NO: 4 (NCBI Ref. Seq. NP__001036221.1).APVRSLHCTLRDAQLKSLVMSGPYELKALHLQGQDLEQQVVFSMSFVQGEESNDKI PVALGLKAKNLYLSCVLKDDKP1I. QLESVDPKNYPKKKMEKRFVFNKIEINNKLEFE SAQFPNWYISTSQAENMPVFLGGTRGGQDITDFTMQFVSS(SEQ ID NO: 4).

[0204] The amino acid of the sequence of the rat (Rattus norvegicus) IL- 1 precursor protein is provided in SEQ ID NO: 5 (GenBank Ref. No. EDL80163.1).MATVTELNCEIAAFDSEENDLFFEADRPQKIKDCFQALDLGCPDESIQLQISQQHLDK SFRKAVSLIVAVEKLWQLPMSCPWSFQDEDPSTFFSFIFEEEPVLCDSWDDDDLLVCD VPIRQLHCRLRDEQQKCLVLSDPCELKALHLNGQNISQQVVFSMSFVQGETSNDKIP98 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOVALGLKGKNLYLSCVMKDGTPTLQLESVDPKQYPKKKMEKRFVFNKIEVKTKVEFE SAQFPNWYISTSQAEHRPVFLGNSNGRDIVDFTMEPVSS(SEQ ID NO: 5)

[0205] The amino acid sequence of the mature rat IL- ip is provided in SEQ ID NO: 6 (GenBank Ref. No. EDL80163.1).IRQLHCRLRDEQQKCLVLSDPCELKALHLNGQNISQQVVFSMSFVQGETSNDKIPVA LGLKGKN LYLSC VMKDG TPTLQLESVDPKQ YPKKKMEKRFVFNKIEVKTKVEFESA QFPNWYISTSQAEHRPVFLGNSNGRDIVDFTME(SEQ ID NO: 6)IL-1β-Mediated Inflammatory Diseases and Disorders

[0206] Due to its association with inflammatory processes, IL-1 P has been implicated in a number of inflammatory diseases and disorders. For example, systemic inhibition of IL- Ip using the anti-IL-1β antibody canakinumab has been shown to exhibit therapeutic efficacy in human patients suffering from atherothrombosis, resulting in significantly lower rates of cardiovascular events as compared to placebo control patients (Ridker et al. J. New Eng. Med.377 (12): 1119-31 (2017)). However, systemic IL- 1 p inhibition using canakinumab is associated with serious safety risks, including fatal infections, sepsis, neutropenia, and leukopenia.

[0207] The present disclosure provides methods and compositions for the treatment of 1L-ip-mediated inflammatory diseases or disorders. In certain embodiments, the IL-lp-mediated inflammatory disease or disorder is osteoarthritis. In certain embodiments, the IL-i -mediated inflammatory disease or disorder is refractory gout. In certain embodiments, the IL-1β-mediated inflammatory disease or disorder is noninfectious uveitis.Osteoarthritis

[0208] In certain embodiments, an IL-l -mediated inflammatory disease or disorder suitable for treatment with the methods and compositions described herein is osteoarthritis.Osteoarthritis is the most common type of arthritis in animals, including humans. In the U. S. alone, there are 32.5 million adul ts with osteoarthritis. Approximately 50% of patients with osteoarthritis of the knee require total joint replacements. Osteoarthritis commonly occurs in humans and is characterized by degenerative changes in the articular cartilage, with loss of 99 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOproteoglycan and collagen and proliferation of new bone formation at articular margins. These changes are accompanied by a variable inflammatory response within the synovial membrane. A principal defect in hyaline cartilage at the articular surface of a joint is the alteration in the ratio of glycosaminoglycans to the collagen fiber content of the matrix.

[0209] Cells of hyaline cartilage known as chondrocytes produce and maintain the surrounding extracellular matrix. Maintenance of homeostasis of the cartilage matrix depends upon catabolism of matrix proteins, such as type II collagen (Col2) and aggrecan. These proteins are digested and replaced by new proteins synthesized by chondrocytes. Catabolism is in part carried out by proteolytic enzymes such as matrix metalloproteinase (MMP) and aggrecanase proteins. In a healthy animal, a balance is achieved between synthesis and degradation, thereby maintaining healthy cartilage. When the balance shifts to degradation, pathogenesis ensues and may result in joint inflammation and osteoarthritis.

[0210] There is yet to be identified a drug that treats the underlying pathology of osteoarthritis. Currently available therapeutic modalities are used to reduce inflammation and to relieve pain. For example, non-steroidal anti-inflammatory drugs (NSAIDs) and intraarticular steroid injections are often used to manage symptoms of osteoarthritis, but these therapies have a variety of drawbacks, including, in particular, gastrointestinal disorders, inhibition of cartilage formation, and / or insufficient or short-lasting relief from symptoms. Recent development of biologic agents targeting IL- Ip for the treatment of osteoarthritis have shown some promise, but present with several high-risk safety concerns.

[0211] The present disclosure provides methods and compositions for the treatmen t of osteoarthritis in a subject e.g., a mammalian subject, such as a human) in need thereof.Refractory gout

[0212] In certain embodiments, an IL-1β-mediated inflammatory disease or disorder sui table for treatment with the methods and compositions described herein is refractory gout. Gout is a form of acute arthritis that causes severe pain and swelling in the joints. Approximately 9,2 million adults in the U. S. are affected by gout. Unlike other rheumatic diseases, the etiology of gout is well-characterized, its pathophysiology is well understood, and the disease is easily diagnosed. For many patients, therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids for acute attacks and prevention of recurrence with agents that lower the serum uric acid levels are highly effective. However, these therapies are not sufficient for many patients with refractory gout due to their lack of adequate clinical efficacy, associated toxicities, or because of co-morbid diseases.100 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO

[0213] Gout is precipitation of uric acid crystals into tissue, usually in and around joints, most often causing recurrent acute or chronic arthritis. The disease is marked by deposits of monosodium urate (MSU) crystals into tissue, usually in and around the joints and in the synovial fluid and lining, and usually an excessive amount of uric acid in the blood. Intense joint inflammation occurs as white blood cells engulf the uric acid crystals, causing pain, heat, and redness of the joint tissues. Gouty arthritis is due to monosodium urate crystal-induced release of proinflammatory cytokines from leukocytes. Among the many cytokines implicated, IL-1 may have a special role in the inflammatory network, as MSU crystals stimulate IL-1 release by monocytes and synovial mononuclear cells. Acute gout flares usually come on suddenly, go away after 5 to 10 days, and can keep recurring.|0214] Studies indicating the apparent involvement of IL-1β and other inflammatory mediators in gout have been published (see e.g., Petrilli et al., Joint Bone Spine (2007) 74:571-576; Pope et al., Arthritis Rheum. (2007) 56:3183-3188; Chen et al,, J. Clin. Invest, (2006) 116:2073-2075; Akahoshi, T., et al., Curr. Opin. Rheumatol. (2007) 19:146-150; Martinon, F., et al., Nature (2006) 440:237-241; and Cronstein et al., Arthritis Res. Ther. (2006) 8, Suppl. 1: S3). So et al., Arthritis Res. Ther. (2007) 9(2): R28 describe the use of a recombinant IL-1 receptor antagonist (IL-IRa, anakinra) in an open label study for the treatment of acute gout, performed with daily dosing of 100 mg subcutaneously for 3 days. McGonagle, et al., Ann. Rheum. Dis. (2007) 66: 1683-1684 describe the use of a recombinant IL-1 receptor antagonist (IL-IRa, anakinra) for the treatment of gout in a patient receiving continuous daily subcutaneous doses of 100 mg. The daily dosing of injectable medications is generally undesirable and may result in problems with patient compliance, thereby decreasing effectiveness of this treatment modality / or limiting its desirability. Thus, there remains a need for effective means to treat gout, particularly treatment compositions and methods that do not require frequent (e.g., daily) injections.|0215] Tire present disclosure provides methods and compositions for the treatment of recurrent gout in a subject (e.g., a mammalian subject, such as a human) in need thereof.Noninfectious uveitis

[0216] In certain embodiments, an IL-1β-mediated inflammatory disease or disorder suitable for treatment with the methods and compositions described herein is noninfectious uveitis. Uveitis (also known as iritis) is an ocular disease characterized by inflammation of the uvea surrounding the iris, ciliary body, and choroid. Inflammation of the retina is also classified as a type of uveitis. Uveitis is classified into anterior (e.g., iritis and iridocyclitis), intermediate 101 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO(e.g., cyclitis and peripheral uveitis), posterior (e.g., choroiditis and retinitis) and total uveitis. It can be anatomically classified into generalized uveitis (e.g., iritis plus intermediate uveitis, chorioretinitis), also called meningitis. Repeated episodes of anterior uveitis can cause permanent and severe damage to the internal structures of the eye. Recurrent anterior uveitis can lead to the formation of substantial peripheral anterior iris synechia and secondary glaucoma. Chronic anterior uveitis can also cause corneal endothelium dysfunction and even cataract formation. Posterior inflammation can lead to persistent pathological vitreous changes and retinal dysfunction, both of which can result in refractory vision loss. Common symptoms of uveitis include vision loss, dark floating spots (floaters), ocular pain, redness of the eye, light sensitivity, and swelling of the eye.10217] Uveitis can be caused by a bacterial or viral infection of the eye (infectious uveitis) or can result from injury' or disease (e.g., AIDS, Behcet’s syndrome, shingles, multiple sclerosis, psoriatic arthritis, rheumatoid arthritis, sarcoidosis, tuberculosis, ulcerative colitis, and Crohn’s disease.

[0218] During acute and chronic inflammation, various mediators of inflammation are released by inflamed tissue and leukocytes. Treatments for typical ocular inflammation target the inflammatory' response. Anti -inflammatory' steroid preparations such as the corticosteroids, prednisolone and dexamethasone are drugs of choice in the treatment of uveitis. Other treatments for eye inflammation include immunomodulatory agents, such as cyclosporine, tacrolimus and sirolimus. However, the use of steroids and other immunomodulatory' agents is complicated by a large number of severe side effects.

[0219] The present disclosure provides methods and compositions for the treatment of noninfectious uveitis in a subject (e.g., a mammalian subject, such as a human) in need thereof.Anti-IL-1β VHH Domains

[0220] Disclosed herein, in certain embodiments, are polypeptides capable of specifically binding to an IL-1β protein (e.g., a human, rhesus macaque, or rat IL-1β protein). In certain embodiments, specific binding of a polypeptide of the disclosure to an IL-1β protein inhibits binding of the IL-1β protein to its cognate receptor. In certain embodiments, the IL-1β protein is a human IL-1β protein. In certain embodiments, the human IL-1β protein comprises the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2 or is a variant thereof having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 1102 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOor SEQ ID NO: 2. In certain embodiments, the IL-1β protein is a rhesus macaque IL-1β protein. In certain embodiments, the rhesus macaque IL-1β protein comprises the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 4 or is a variant thereof having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 3 or SEQ ID NO: 4, In certain embodiments, the IL-1β protein is rat IL-1β protein. In certain embodiments, the rat IL-1β protein comprises the amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 6 or is a variant thereof having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 5 or SEQ ID NO: 6.|0221 ] In certain embodiments, the polypeptide that binds IL-1β comprises a VHH that binds.

[0222] In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having at least 80% sequence identity to any one of SEQ ID NOs: 10-182 and 6813-6817. In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having at least 85% sequence identity to any one of SEQ ID NOs: 10-182 and 6813-6817. In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 10-182 and 6813-6817. In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having at least 95% sequence identity to any one of SEQ ID NOs: 10-182 and 6813-6817. In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having 100% sequence identity to any one of SEQ ID NOs: 10-182 and 6813-6817. In certain embodiments, a VHH that binds to IL-1β consists of an amino acid sequence having 100% sequence identity to any one of SEQ ID NOs: 10-182 and 6813-6817.

[0223] In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 10. In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 10. In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 10. In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 10. In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having 100% sequence identity to SEQ ID NO: 10. In certain embodiments, a VHH that binds to IL-1β consists of an amino acid sequence having 100% sequence identity to SEQ ID NO: 10.103 / 647IPTS / 200261047.5Attorney Docket: AVT-001WO

[0224] In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 11. In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 11. In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 11. In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 11. In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having 100% sequence identity to SEQ ID NO: 11. In certain embodiments, a VHH that binds to IL-1β consists of an amino acid sequence having 100% sequence identity to SEQ ID NO: 11.

[0225] In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 12. In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 12. In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 12. In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 12. In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having 100% sequence identity to SEQ ID NO: 12. In certain embodiments, a VHH that binds to IL-1β consists of an amino acid sequence having 100% sequence identity to SEQ ID NO: 12.

[0226] In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 13. In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 13. In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 13. In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 13. In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having 100% sequence identity to SEQ ID NO: 13. In certain embodiments, a VHH that binds to IL-1β consists of an amino acid sequence having 100% sequence identity to SEQ ID NO: 13.

[0227] In certain embodiments, a VHH that binds to IL- 1 P comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 14. In certain embodiments, a VHH that binds to IL- 1 p comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 14. In certain embodiments, a VHH that binds to IL- 1 p comprises an 104 / 647IPTS / 200261047.5Attorney Docket: AVT-001WOamino acid sequence having at least 90% sequence identity to SEQ ID NO: 14. In certain embodiments, a VHH that binds to IL- 1 p comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 14. In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having 100% sequence identity to SEQ ID NO: 14. In certain embodiments, a VHH that binds to IL- 1 consists of an amino acid sequence having 100% sequence identity to SEQ ID NO: 14.

[0228] In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 15. In certain embodiments, a VHH that binds to IL-1β comprises an amino acid sequen...

Claims

1. Attorney Docket: AVT-001 WOCLAIMS1. A bispecific polypeptide, comprising:(c) at least one first immunoglobulin single variable domain (ISVD), wherein the first ISVD specifically binds to Interleukin 1 Beta (IL- 1 p); and(d) at least one second ISVD, wherein the second ISVD specifically binds to Type II Collagen (Col2),2. The bispecific polypeptide of claim 1, comprising two second ISVDs that specifically bind to Col2.

3. The bispecific polypeptide of claim 2, comprising one first ISVD that specifically binds to IL- 1 and two second ISVDs that specifically bind to Col2.

4. The bispecific polypeptide of any one of claims 1-3, wherein tire first ISVD and the second ISVD are each independently a VHH.

5. The bispecific polypeptide of any one of claims 1-4, wherein the first ISVD comprises a complementarity determining region 1 (CDR1) comprising an amino acid sequence of any one of SEQ ID NOs: 2155-2327 and 6863-6867, a CDR2 comprising an amino acid sequence of any one of SEQ ID NOs: 2501-2673 and 6873-6877, and a CDR3 comprising an amino acid sequence of any one of SEQ ID NOs: 2847-3019 and 6883-6887.

6. Hie bispecific polypeptide of any one of claims 1-5, wherein the first ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 2045, a CDR2 comprising an amino acid sequence of SEQ ID NO: 2391, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 2737.

7. The bispecific polypeptide of any one of claims 1-5, wherein the first ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 2046, a CDR2 comprising an amino acid sequence of SEQ ID NO: 2392, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 2738.

8. The bispecific polypeptide of any one of claims 1-5, wherein the first ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 2047, a CDR2 comprising an 628 / 647IPTS / 200261047.5Attorney Docket: AVT-001 WOamino acid sequence of SEQ ID NO: 2393, and a CDR3 comprising an amino acid sequence ofSEQ ID NO: 2739.

9. The bispecific polypeptide of any one of claims 1-5, wherein the first ISVD comprises a CDR1 comprising an amino acid sequence ofSEQ ID NO: 2048, a CDR2 comprising an amino acid sequence of SEQ ID NO: 2394, and a CDR3 comprising an amino acid sequence ofSEQ ID NO: 2770.

10. The bispecific polypeptide of any one of claims 1-5, wherein the first ISVD comprises a CDRI comprising an amino acid sequence ofSEQ ID NO: 2123, a CDR2 comprising an amino acid sequence of SEQ ID NO: 2469, and a CDR3 comprising an amino acid sequence ofSEQ ID NO: 2815.

11. The bispecific polypeptide of any one of claims 1-5, wherein the first ISVD comprises a CDRI comprising an amino acid sequence ofSEQ ID NO: 2124, a CDR2 comprising an amino acid sequence of SEQ ID NO: 2470, and a CDR3 comprising an amino acid sequence ofSEQ ID NO: 2816.

12. The bispecific polypeptide of any one of claims 1-5, wherein the first ISVD comprises a CDRI comprising an amino acid sequence ofSEQ ID NO: 2125, a CDR2 comprising an amino acid sequence of SEQ ID NO: 2471, and a CDR3 comprising an amino acid sequence ofSEQ ID NO: 2817.

13. The bispecific polypeptide of any one of claims 1-5, wherein the first ISVD comprises a CDRI comprising an amino acid sequence ofSEQ ID NO: 6863, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6873, and a CDR3 comprising an amino acid sequence ofSEQ ID NO: 6883.

14. The bispecific polypeptide of any one of claims 1-5, wherein the first ISVD comprises a CDRI comprising an amino acid sequence ofSEQ ID NO: 6864, a CDR2 comprising an amino acid sequence ofSEQ ID NO: 6874, and a CDR3 comprising an amino acid sequence ofSEQ ID NO: 6884.

15. The bispecific polypeptide of any one of claims 1-5, wherein the first ISVD comprises a CDRI comprising an amino acid sequence ofSEQ ID NO: 6865, a CDR2 comprising an 629 / 647IPTS / 200261047.5Attorney Docket: AVT-001 WOamino acid sequence of SEQ ID NO: 6875, and a CDR3 comprising an amino acid sequence ofSEQ ID NO: 6885.

16. The bispecific polypeptide of any one of claims 1-5, wherein the first ISVD comprises a CDR1 comprising an amino acid sequence ofSEQ ID NO: 6866, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6876, and a CDR3 comprising an amino acid sequence ofSEQ ID NO: 6886.

17. lire bispecific polypeptide of any one of claims 1-5, wherein the first ISVD comprises a CDR1 comprising an amino acid sequence ofSEQ ID NO: 6867, a CDR2 comprising an amino acid sequence of SEQ ID NO: 6877, and a CDR3 comprising an amino acid sequence ofSEQ ID NO: 6887.

18. The bispecific polypeptide of any one of claims 1-17, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of any one of SEQ ID NOs: 5209-5330 and 6976-6999, a CDR2 comprising an amino acid sequence of any one of SEQ ID NOs: 5453-5574 and 7024-7047, and a CDR3 comprising an amino acid sequence of any one ofSEQ ID NOs: 5697-5818 and 7072-7095.

19. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 5225, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5469, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5713.

20. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 5256, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5500, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5744.

21. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 5284, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5528, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5772.630 / 647IPTS / 200261047.5Attorney Docket: AVT-001 WO22. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 5303, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5547, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5791.

23. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 5307, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5551, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5795.

24. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7144, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7192, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7240.

25. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7145, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7193, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7241.

26. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7146, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7194, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7242.

27. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7147, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7195, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7243.

28. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7148, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7196, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7244,631 / 647IPTS / 200261047.5Attorney Docket: AVT-001 WO29. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7149, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7197, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7245.

30. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7150, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7198, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7246,31. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR 1 comprising an amino acid sequence of SEQ ID NO: 7151, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7199, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7247.

32. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7152, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7200, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7248.

33. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7153, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7201, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7249.

34. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7154, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7202, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7250.

35. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7155, a CDR2632 / 647IPTS / 200261047.5Attorney Docket: AVT-001 WOcomprising an amino acid sequence of SEQ ID NO: 7203, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7251.

36. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7156, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7204, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7252.

37. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7157, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7205, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7253.

38. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7158, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7206, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7254,39. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7159, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7207, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7255.

40. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7160, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7208, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7256.

41. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7161, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7209, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7257.633 / 647IPTS / 200261047.5Attorney Docket: AVT-001 WO42. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7162, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7210, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7258.

43. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7163, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7211, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7259.

44. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7164, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7212, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7260.

45. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7165, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7213, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7261.

46. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7166, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7214, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7262,47. The bispecific polypeptide of any one of claims 1-18, wherein the second ISVD comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 7167, a CDR2 comprising an amino acid sequence of SEQ ID NO: 7215, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 7263.

48. The bispecific polypeptide of any one of claims 1-47, wherein the first ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to any one of SEQ ID NOs: 10-182 and 6813-6817.634 / 647IPTS / 200261047.5Attorney Docket: AVT-001 WO49. The bispecific polypeptide of any one of claims 1-47, wherein the first ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 71,50. The bispecific polypeptide of any one of claims 1-47, wherein the first ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 72.

51. The bispecific polypeptide of any one of claims 1-47, wherein the first ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 73.

52. The bispecific polypeptide of any one of claims 1-47, wherein the first ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 74,53. The bispecific polypeptide of any one of claims 1-47, wherein the first ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 149.

54. The bispecific polypeptide of any one of claims 1-47, wherein the first ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 150.

55. The bispecific polypeptide of any one of claims 1-47, wherein the first ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 151.

56. The bispecific polypeptide of any one of claims 1-47, wherein the first ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6813.635 / 647IPTS / 200261047.5Attorney Docket: AVT-001 WO57. The bispecific polypeptide of any one of claims 1-47, wherein the first ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6814.

58. The bispecific polypeptide of any one of claims 1-47, wherein the first ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6815.

59. The bispecific polypeptide of any one of claims 1-47, w herein the first ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity’ to SEQ ID NO: 6816,60. The bispecific polypeptide of any one of claims 1-47, wherein the first ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6817.

61. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to any one of SEQ ID NOs: 356-477 and 6928-6951.

62. The bispecific polypeptide of any one of claims 1-60, w’herein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 372.

63. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 403.

64. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 431.

65. The bispecific polypeptide of any one of claims 1-60, w’herein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 450.636 / 647IPTS / 200261047.5Attorney Docket: AVT-001 WO66. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 454.

67. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6928.

68. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6929.

69. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6930.

70. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6931.

71. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6932.

72. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6933.

73. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6934.637 / 647IPTS / 200261047.5Attorney Docket: AVT-001 WO74. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6935.

75. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6936.

76. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6937.

77. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6938.

78. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6939.

79. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6940.

80. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6941.

81. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6942.638 / 647IPTS / 200261047.5Attorney Docket: AVT-001 WO82. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6943.

83. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD consists of an amino acid sequence of SEQ ID NO: 6943,84. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6945.

85. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6946.

86. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6947.

87. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6948.

88. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6949.

89. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6950.

90. The bispecific polypeptide of any one of claims 1-60, wherein the second ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to SEQ ID NO: 6951.639 / 647IPTS / 200261047.5Attorney Docket: AVT-001 WO91. The bispecific polypeptide of any one of claims 1-60, comprising a first ISVD comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NO: 6813, and a second ISVD comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NO: 6928.

92. The bispecific polypeptide of any one of claims 1-60, comprising a first ISVD comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NO: 6813, and a second ISVD comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NO: 6929.

93. The bispecific polypeptide of any one of claims 1-60, comprising a first ISVD comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NO: 6813, and a second ISVD comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NO: 6931.

94. The bispecific polypeptide of any one of claims 1-60, comprising a first ISVD comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NO: 6813, and a second ISVD comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to SEQ ID NO: 6932.

95. The bispecific polypeptide of any one of claims 1-94, wherein the first ISVD and the second ISVD are connected by a peptide linker.

96. The bispecific polypeptide of claim 95, wherein the peptide linker comprises an amino acid sequence having at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to the amino acid sequence of any one of SEQ ID NOs: 6795-6804.

97. The bispecific polypeptide of claim 95 or 96, wherein the peptide linker comprises an amino acid sequence of SEQ ID NO: 6796.640 / 647IPTS / 200261047.5Attorney Docket: AVT-001 WO98. The bispecific polypeptide of any one of claims 1-97, comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more to any one of SEQ ID NOs: 7456-7471.

99. The bispecific polypeptide of any one of claims 1-98, wherein the first ISVD specifically binds to IL-1β with a dissociation rate (koff) between 1 * 10'1s‘1and 2.2x 10 s4.

100. The bispecific polypeptide of any one of claims 1-99, wherein the first ISVD specifically binds to IL-lp with a dissociation constant (KD) of between 1.1 * 10'7M and 2.4* IO’10M, as measured by surface plasmon resonance (SPR),101. The bispecific polypeptide of any one of claims 1-100, wherein the first ISVD inhibits binding of IL- 1 to Interleukin 1 Receptor Type 1 (IL-1R1) with an ICso that is between 80 nM and 340 nM.

102. The bispecific polypeptide of any one of claims 1-101, w herein the bispecific polypeptide is cross-reactive with human IL- ip and IL- 1 P of at least one other mammalian species.

103. The bispecific polypeptide of any one of claims 1-102, wherein tire bispecific polypeptide is cross-reactive with human Col2 and Col2 of at least one other mammalian species.

104. The bispecific polypeptide of claim 102 or 103, wherein the at least one other mammalian species is a rodent or a non-human primate.

105. lire bispecific polypeptide of claim 104, wherein the rodent is a rat.

106. The bispecific polypeptide of claim 104, wherein the non-human primate is a rhesus macaque.

107. The bi specific polypeptide of any one of claims 1-106, wherein the bispecific polypeptide has a melting temperature of 50°C or greater.641 / 647IPTS / 200261047.5Attorney Docket: AVT-001 WO108. The bispecific polypeptide of any one of claims 1-107, wherein the bispecific polypeptide has an isoelectric point (pl) of greater than 6, greater than 7, or greater than 8.

109. The bispecific polypeptide of any one of claims 1-108, wherein first IS VD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1 p.

110. The bispecific polypeptide of claim 109, wherein the reference antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to any one of SEQ ID NOs: 10-182 and 6813-6817,111. The bispecific polypeptide of any one of claims 1-110, wherein the second IS VD competes for binding with a reference anti-Col2 antibody to an epitope of Col2.

112. The bispecific polypeptide of claim 111, wherein the reference antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to any one of SEQ ID NOs: 356-477 and 6928-6951.

113. A pharmaceutical composition comprising the bispecific polypeptide of any one of claims 1-112 and a pharmaceutically acceptable carrier, diluent, or excipient.

114. A nucleic acid encoding the bispecific polypeptide of any one of claims 1-112,115. An expression vector comprising the nucleic acid of claim 114.

116. A host cell comprising the nucleic acid of claim 114 or the expression vector of claim 115.

117. A method of treating a disease or disorder in a subject, the method comprising administering to the subject the bispecific polypeptide of any one of claims 1 -112 or the pharmaceutical composition of claim 113.

118. The method of claim 117, wherein the disease or disorder is an inflammatory’ disease or disorder.642 / 647IPTS / 200261047.5Attorney Docket: AVT-001 WO119. The method of claim 118, wherein the inflammatory disease or disorder is an IL- 1 P~ mediated disease or disorder.

120. The method of claim 119, wherein the IL-1β-mediated inflammatory disease or disorder is osteoarthritis,121. The method of claim 119, wherein the IL-1 -mediated inflammatory disease or disorder is refractory gout.

122. The method of claim 119, wherein the IL-1β-mediated inflammatory disease or disorder is non-infectious uveitis.

123. The method of any one of claims 117-122, wherein the bispecific polypeptide or the pharmaceutical composition are administered by way of systemic administration.

124. The method of any one of claims 117-122, wherein the bispecific polypeptide or the pharmaceutical composi tion are administered by way of local administration.

125. The method of claim 124, wherein local administration compri ses intra-articular administration.

126. A bispecific agent, comprising:(c) at least one first means for specifically binding to IL- IP; and(d) at least one second means for specifically binding to Col2.

127. The bispecific agent of claim 126, comprising two second means for specifically binding to Col2.

128. Hie bispecific agent of claim 126 or 127, wherein the at least one first means for specifically binding to IL- ip and the at least one second means for specifically binding to CoI2 are connected by a linker.

129. An ISVD that specifically binds to IL- 1 p.643 / 647IPTS / 200261047.5Attorney Docket: AVT-001 WO130. The ISVD of claim 129, wherein the ISVD is a VHH.

131. The ISVD of claim 129 or 130, wherein the ISVD comprises a CDR1 comprising an amino acid sequence of any one of SEQ ID NOs: 2155-2327 and 6863-6867, a CDR2 comprising an amino acid sequence of SEQ ID NO: 2501-2673 and 6873-6877, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 2847-3019 and 6883-6887.

132. lire ISVD of any one of claims 129-131, wherein the ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to any one of SEQ ID NOs: 10-182 and 6813-6817.

133. Tire ISVD of any one of claims 129-132, wherein the ISVD specifically binds to IL- 1 p with a koff between 1x10⁻⁴s'1and 2.2 - 10'4s‘!.

134. The ISVD of any one of claims 129-133, wherein the ISVD specifically binds to IL- i with a KD of between 1.1 x 10'7M and 2.4* 1 O’10M, as measured by SPR.

135. The ISVD of any one of claims 129-134, wherein the ISVD inhibits binding of IL-i to IL-1R1 with an ICso that is between 80-340 nM.

136. The ISVD of any one of claims 129-135, wherein the ISVD is cross-reactive with human IL- 1 p and IL-1 of at least one other mammalian species.

137. The ISVD of claim 136, wherein the at least one other mammalian species is a rodent or a non-human primate.

138. lire ISVD of claim 137, wherein the rodent is a rat.

139. The ISVD of claim 137, wherein the non-human primate is a rhesus macaque.

140. The ISVD of any one of claims 129-139, wherein the ISVD has a melting temperature of at least 50°C,644 / 647IPTS / 200261047.5Attorney Docket: AVT-001 WO141. The ISVD of any one of claims 129-140, wherein the ISVD competes for binding with an anti-IL-1β reference antibody to an epitope of IL-1β.

142. The ISVD of claim 141, wherein the anti-IL-lp reference antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to any one of SEQ ID NOs: 10-182 and 6813-6817,143. Tire ISVD of any one of claims 129-142, further comprising an Fc region.

144. An ISVD that specifically binds to Col2,145. The ISVD of claim 144, wherein the ISVD is a VHH146. The ISVD of claim 144 or 145, wherein the ISVD comprises a CDR1 comprising an amino acid sequence of any one of SEQ ID NOs: 5209-5330 and 6976-6999, a CDR2 comprising an amino acid sequence of SEQ ID NO: 5453-5574 and 7024-7047, and a CDR3 comprising an amino acid sequence of SEQ ID NO: 5697-5818 and 7072-7095.

147. The ISVD of any one of claims 144-146, wherein the ISVD comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to any one of SEQ ID NOs: 356-477 and 6928-6951.

148. Die ISVD of any one of claims 144-147, wherein the ISVD is cross-reactive with human Col2 and Col2 of at least one other mammalian species.

149. The ISVD of claim 148, wherein the at least one other mammalian species is a rodent or a non-human primate.

150. The ISVD of claim 149, wherein the rodent is a rat.

151. Tire ISVD of claim 149, wherein the non-human primate is a rhesus macaque,152. The ISVD of any one of claims 144-151, wherein the ISVD has a melting temperature of at least 50°C.645 / 647IPTS / 200261047.5Attorney Docket: AVT-001 WO153. The ISVD of any one of claims 144-152, wherein the ISVD competes for binding with a reference anti-Co!2 antibody to an epitope of Col2.

154. The bispecific polypeptide of claim 153, wherein the anti-Co!2 reference antibody comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 99%, or more sequence identity to any one of SEQ ID NOs: 356-477 and 6928-6951.

155. The ISVD of any one of claims 144-154, further comprising an Fc region.646 / 647IPTS / 200261047.5

Images