Engineered antibodies that bind LAG3
The present disclosure provides fully human anti-LAG3 IgG class antibodies engineered to have amino acid sequence in their heavy chain variable region and/or light chain variable region to improve antigen binding, cell binding, T cell activation and cytokine release capabilities.
1 . A LAG3-binding protein comprising a heavy chain variable region and a light chain variable region, wherein
the heavy chain variable region comprises the CDR1, CDR2, and CDR3 sequences present in SEQ ID NO: 4 and the light chain variable region comprises the CDR1, CDR2, and CDR3 sequences present in SEQ ID NO: 5; or
the heavy chain variable region comprises the CDR1, CDR2, and CDR3 sequences present in SEQ ID NO: 6 and the light chain variable region comprises the CDR1, CDR2, and CDR3 sequences present in SEQ ID NO:7; or
the heavy chain variable region comprises the CDR1, CDR2, and CDR3 sequences present in SEQ ID NO: 8 and the light chain variable region comprises the CDR1, CDR2, and CDR3 sequences present in SEQ ID NO: 9; or
the heavy chain variable region comprises the CDR1, CDR2, and CDR3 sequences present in SEQ ID NO: 10 and the light chain variable region comprises the CDR1, CDR2, and CDR3 sequences present in SEQ ID NO: 11;
wherein the heavy chain region CDR1, CDR2, and CDR3 sequences, and the light chain variable region CDR1, CDR2, and CDR3 sequences are defined according to Kabat, Chothia, or IMGT numbering system,
and optionally wherein the LAG3-binding protein is an antibody or an antigen-binding fragment thereof.
2 . The LAG3-binding protein of claim 1 , wherein the heavy chain variable region and the light chain variable region comprise the sequence of SEQ ID NOS: 4 and 5, SEQ ID NOS: 6 and 7, SEQ ID NOS: 8 and 9, or SEQ ID NOS: 10 and 11, respectively.
3 . The LAG3-binding protein of claim 1 , which is a fully human anti-LAG3 Fab fragment.
4 . The LAG3-binding protein of claim 1 , which is a single chain human anti-LAG3 antibody, and optionally wherein the variable domain region from a heavy chain and the variable domain region from a light chain are joined together with a peptide linker.
5 . The LAG3-binding protein of claim 4 , wherein the heavy chain variable region and the light chain variable region comprise the sequence of SEQ ID NOS: 4 and 5, SEQ ID NOS: 6 and 7, SEQ ID NOS: 8 and 9, or SEQ ID NOS: 10 and 11, respectively.
6 . The LAG3-binding protein of claim 1 , wherein the LAG3-binding protein binds human LAG3 with a K D of 10 −8 M or less; or wherein the LAG3-binding protein binds cynomolgus LAG3 with a K D of 10 −6 M or less.
7 . The LAG3-binding protein of claim 1 , comprising an IgG4 class antibody.
8 . A pharmaceutical composition comprising a pharmaceutically-acceptable excipient and the LAG3-binding protein of claim 1 .
9 . A kit comprising the LAG3-binding protein of claim 1 .
10 . A nucleic acid that encodes (a) (i) the heavy chain variable region of the LAG3-binding protein of claim 1 , and (ii) the light chain variable region of the LAG3-binding protein of claim 1 ; or (b) the LAG3-binding protein of claim 1 .
11 . A vector comprising the nucleic acid of claim 10 .
12 . A host cell comprising the vector of claim 11 , optionally wherein the vector comprises an expression vector, and wherein the host cell expresses the heavy and the light chain variable regions.
13 . A method for preparing a LAG3-binding protein, the method comprising: culturing a population of the host cell of claim 12 under conditions suitable for expressing the LAG3-binding protein, and
optionally further comprising: recovering from the host cells the expressed LAG3-binding protein.
14 . A method of treating a disease associated with LAG3 over-expression in a subject in need thereof, comprising administering the LAG3-binding protein of claim 1 to the subject.
15 . The method of claim 14 , wherein the disease is bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, carcinoma of fallopian tubes, carcinoma of endometrium, carcinoma of cervix, carcinoma of vagina, carcinoma of vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of esophagus, cancer of small intestine, cancer of endocrine system, cancer of thyroid gland, cancer of parathyroid gland, cancer of adrenal gland, sarcoma of soft tissue, cancer of urethra, cancer of penis, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of bladder, cancer of kidney or ureter, carcinoma of renal pelvis, neoplasm of central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancer, or a cancer induced by asbestos.
16 . The LAG3-binding protein of claim 2 , which is a fully human anti-LAG3 Fab fragment.