Therapeutic molecules that bind to LAG3 and PD1
Inventors
Edwards, Carolyn • SETTE, Angelica • OSUCH, Isabelle • TENG, Yumin • Legg, James • Escors Murugarren, David
Assignees
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Publication Number
US-11951172-B2
Publication Date
2024-04-09
Expiration Date
Abstract
The invention relates to LAG-3 binding agents, in particular variable heavy chain (VH) sdAbs and bispecific agents that target both LAG-3 and PD-1, and the use of such binding agents in the treatment, prevention and detection of disease.
Core Innovation
The disclosure describes an isolated human heavy chain variable domain (V_H) single domain antibody that binds to human LAG-3. The binding is defined by specific CDR1, CDR2, and CDR3 sequences referenced to SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, with allowed point substitutions at stated CDR positions, including Y to F in CDR1 at position 32 and multiple substitutions in CDR2 and CDR3.
A further aspect provides an isolated binding agent comprising a first (V_H) single domain antibody and a second (V_H) single domain antibody that both bind to human LAG-3, where the first and/or second antibodies include the CDR-defined LAG-3-binding sequences and allowed substitutions as specified. The multispecific concept extends the LAG-3-binding capability by pairing a LAG-3 binder with a PD-1-binding moiety, including constructions described as CAR constructs using isolated anti-LAG-3 VH sdAbs or PD-1/LAG-3 multispecific binding agents.
The disclosed therapeutic framework defines treatment and prevention of disease using effective amounts, including parenteral dosage unit and oral composition concepts, and broad disease and cancer indications including immune and neurological diseases. The document also identifies predictive and prognostic biomarkers for bispecific anti-LAG plus anti-PD1 therapy, including Cbl-b and/or c-Cbl, linked to measuring protein or RNA expression and using a risk score approach to predict response, with diagnostic and kit concepts for detecting LAG-3.
Claims Coverage
The independent claims cover the isolated human LAG-3-binding V_H single domain antibody and isolated binding agents comprising two LAG-3-binding V_H single domain antibodies. The inventive features are grounded in SEQ ID-referenced CDR sequence requirements and enumerated point substitutions, with broader summary coverage described for multispecific constructs, CAR constructs, pharmaceutical formats, treatment, and biomarker and diagnostic concepts.
LAG-3-binding isolated human V_H single domain antibody with SEQ ID-defined CDRs
An isolated human heavy chain variable domain (V_H) single domain antibody that binds to human LAG-3 comprising CDR1, CDR2, and CDR3 sequence requirements referenced to SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, with allowed point substitutions at stated CDR positions.
Two V_H single-domain LAG-3-binding antibodies in an isolated binding agent
An isolated binding agent comprising a first (V_H) single domain antibody that binds to human LAG-3 and a second (V_H) single domain antibody that binds to human LAG-3, wherein the first and/or second antibody includes the specified CDR1, CDR2, and CDR3 sequence requirements and allowed substitutions.
Overall, the independent claims primarily claim isolated human LAG-3-binding V_H single-domain antibodies and isolated binding agents made from two such V_H single-domain antibodies, with the scope defined by SEQ ID-referenced CDR1, CDR2, and CDR3 sequence frameworks and point-substitution combinations. The document summary further indicates broader claim coverage including multispecific binding agents with PD-1, CAR constructs, pharmaceutical formats, and biomarker and diagnostic concepts for bispecific anti-LAG plus anti-PD1 response prediction.
Stated Advantages
Selective targeting of PD-1+LAG-3+ dysfunctional TIL.
Potential improved safety relative to conventional Fc-containing combination therapies.
Overcoming PD-1 resistance.
Addresses scFv-based CAR-T issues including stability, aggregation, constitutive signalling, and immunogenicity.
Documented Applications
Therapeutic use in treating cancer, with cancers explicitly listed including bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, breast cancer, brain cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, kidney cancer, renal cancer, sarcoma of soft tissue, cancer of the urethra, cancer of the bladder, urothelial carcinoma, lung cancer, non-small cell lung cancer, thymoma, leukemia, prostate cancer, mesothelioma, adrenocortical carcinoma, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma, and multiple myeloma.
Therapeutic and diagnostic applications across immune and neurological conditions.
Therapeutic use for treatment or prevention of disease including cancer, immune disease, and neurological disease or synucleinopathy, including alpha-synuclein contexts.
Combination therapy contexts.
Diagnostic and kit concepts for detecting LAG-3.
Predictive and prognostic biomarker use with Cbl-b and/or c-Cbl for bispecific anti-LAG plus anti-PD1 therapy response prediction using protein or RNA measurement and a risk score approach.
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