Formulations of single domain antigen binding molecules
The invention relates to formulations of single domain antigen binding molecules, e.g., nanobody molecules, in particular formulations of TNF-binding nanobody molecules. The single domain antigen binding molecules can include one or more single binding domains that interact with, e.g., bind to, one or more target proteins. The formulations are useful, e.g., as pharmaceutical formulations. Method of preparing, and using the formulations described herein, to treat, e.g., TNF-associated disorders, are also disclosed.
1. A formulation comprising:
(a) a single domain antigen binding (SDAB) molecule at a concentration from about 0.1 mg/mL to about 350 mg/mL, comprising one or more single domain molecules, wherein at least one of the single domain molecule binds to human serum albumin (HSA) and comprises three CDRs having the amino sequences: SFGMS (SEQ ID NO: 5) (CDR1), SISGSGSDTLYADSVKG (SEQ ID NO: 6) (CDR2) and GGSLSR (SEQ ID NO: 7) (CDR3);
(b) a lyoprotectant; and
(c) a histidine buffer at a concentration about 5 to about 50 mM, such that the pH of the formulation is about 5.0 to 7.5.
2. The formulation of claim 1 , wherein the at least one single domain molecule that binds to HSA is selected from the group consisting of:
single domain molecules comprising a variable region having the amino acid sequence from about amino acids 125 to 239 of SEQ ID NO: 1,
single domain molecules comprising a variable region that differs by up to 10 amino acids from said variable region,
single domain molecules having at least 85%, 90%, 95% or more amino acid identity relative to the amino acid sequence shown in SEQ ID NO: 1, and
single domain molecules having up to 20, 15, 10, 5, 4, 3, 2, or 1 amino acid changes relative to the amino acid sequence shown in SEQ ID NO: 1.
3. The formulation of claim 1 , wherein the SDAB molecule is chosen from the group consisting of monovalent, multivalent, bivalent, trivalent, tetravalent, monospecific, multispecific, bispecific, trispecific and tetraspecific SDAB molecules.
4. The formulation of claim 1 , wherein the at least one single domain molecule that binds to HSA is ALB1, ALB6, ALB7, ALB8, ALB9, or ALB10 disclosed in U.S. Pat. No. 8,703,131.
5. The formulation of claim 1 , wherein said lyoprotectant is selected from the group consisting of
sugars, optionally sucrose, sorbitol, and/or trehalose;
amino acids, optionally monosodium glutamate and/or histidine;
methylamines, optionally betaine;
lyotrophic salts, optionally magnesium sulfate;
polyols, optionally trihydric sugar alcohols and/or higher sugar alcohols, including glycerin, erythritol, glycerol, arabitol, xylitol, and/or mannitol;
propylene glycol;
polyethylene glycol;
pluronics; and
combinations thereof.
6. The formulation of claim 1 , wherein the SDAB molecule further comprises at least one or two single domain molecules that bind to tumor necrosis factor alpha (TNFα).
7. The formulation of claim 1 , wherein the SDAB molecule further comprises one or more single domain molecules that is useful in treating autoimmune disorders, arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, polyarticular juvenile idiopathic arthritis (JIA), psoriatic arthritis, lupus-associated arthritis, ankylosing spondylitis, scleroderma, systemic lupus erythematosis, Sjogren's syndrome, vasculitis, multiple sclerosis, autoimmune thyroiditis, dermatitis, atopic dermatitis, eczematous dermatitis, myasthenia gravis, inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, diabetes mellitus (type I diabetes), inflammatory conditions of the skin, psoriasis, acute inflammatory conditions, endotoxemia, sepsis, septicaemia, toxic shock syndrome, infectious disease, transplant rejection, and allergy.
8. A kit or an article of manufacture, comprising a container containing the formulation of claim 1 , and instructions for use.
9. The kit or article of manufacture of claim 8 , wherein the formulation is present in a vial or an injectable syringe.