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Publication Number
US-10640576-B2
Publication Date
2020-05-05
Expiration Date
Abstract
The present disclosure is broadly concerned with the field of cancer immunotherapy. For example, the present disclosure generally related to a binding molecule comprising antibody variable light (VL) regions, variable heavy (VH) regions, constant heavy 1 (CH1) regions, and light chain constant (CL) regions that are configured to form two antigen binding Fab regions and an antigen binding Fv region so that the binding molecule binds to two different antigens.
Core Innovation
The invention provides a binding molecule comprising first and second antigen binding Fab regions and an antigen binding Fv region. The first Fab region and the second Fab region bind Programmed Death-Ligand 1 (PD-L1), while the Fv region binds Cluster of Differentiation 3 (CD3). The binding molecule is defined as an antibody construct formed from multiple polypeptides that include antibody light chains and variable heavy and variable light regions.
The first polypeptide and the first VH region and the first CH1 region of the third polypeptide form a first antigen binding Fab region, and the second polypeptide and the third VH region and the second CH1 region of the fourth polypeptide form a second antigen binding Fab region. The Fv region is formed by the second VH region of the third polypeptide and the VL region of the fourth polypeptide. The antibody light chains each comprise three Complementarity Determining Regions (CDRs) having amino acid sequences of SEQ ID NO.: 9, SEQ ID NO.: 10, and SEQ ID NO.: 11.
The invention further fixes specific VH and VL CDR compositions using SEQ ID NO. references, including the third polypeptide first VH region CDRs having amino acid sequences of SEQ ID NO.: 5, SEQ ID NO.: 6, and SEQ ID NO.: 7, the second VH region CDRs having amino acid sequences of SEQ ID NO.: 13, SEQ ID NO.: 14, and SEQ ID NO.: 15 or alternative SEQ ID NO.: 78, SEQ ID NO.: 79, and SEQ ID NO.: 80, and the fourth polypeptide third VH region CDRs having amino acid sequences of SEQ ID NO.: 5, SEQ ID NO.: 6, and SEQ ID NO.: 7 and VL region CDRs having amino acid sequences of SEQ ID NO.: 17, SEQ ID NO.: 18, and SEQ ID NO.: 19 or alternative SEQ ID NO.: 82, SEQ ID NO.: 83, and SEQ ID NO.: 87.
Claims Coverage
Two independent claims are identified. Both claims define a binding molecule architecture with two antigen binding Fab regions and one antigen binding Fv region, with inventive features fixed by specific CDR sequence assignments via SEQ ID NOs and by the antigen-binding specificities PD-L1 for the Fab regions and CD3 for the Fv region.
Two fab regions binding PD-L1 and an Fv region binding CD3
A binding molecule comprising first and second polypeptides each comprising an antibody light chain, a third polypeptide having, in order from N-terminus to C-terminus, a first VH region and a first CH1 region and a second VH region, and a fourth polypeptide having, in order from N-terminus to C-terminus, a third VH region and a second CH1 region and a VL region, wherein the first polypeptide and the first VH region and the first CH1 region of the third polypeptide form a first antigen binding Fab region; wherein the second polypeptide and the third VH region and the second CH1 region of the fourth polypeptide form a second antigen binding Fab region; wherein the second VH region of the third polypeptide and the VL region of the fourth polypeptide form an antigen binding Fv region; and wherein the first Fab region and the second Fab region bind Programmed Death-Ligand 1 (PD-L1), and the Fv region binds Cluster of Differentiation 3 (CD3).
Specific light-chain CDR sequence set
A binding molecule wherein the antibody light chains of the first and the second polypeptides each comprise three Complementarity Determining Regions (CDRs) having amino acid sequences of SEQ ID NO.: 9, SEQ ID NO.: 10, and SEQ ID NO.: 11.
Specific vh and vl CDR sequence sets
A binding molecule wherein, in the third polypeptide, the first VH region comprises three CDRs having amino acid sequences of SEQ ID NO.: 5, SEQ ID NO.: 6, and SEQ ID NO.: 7, and the second VH region comprises three CDRs having amino acid sequences of SEQ ID NO.: 13, SEQ ID NO.: 14, and SEQ ID NO.: 15; and wherein in the fourth polypeptide, the third VH region comprises three CDRs having amino acid sequences of SEQ ID NO.: 5, SEQ ID NO.: 6, and SEQ ID NO.: 7, and the VL region comprises three CDRs having amino acid sequences of SEQ ID NO.: 17, SEQ ID NO.: 18, and SEQ ID NO.: 19.
Alternative vh and vl cdr sequence sets
A binding molecule wherein, in the third polypeptide, the first VH region comprises three CDRs having amino acid sequences of SEQ ID NO.: 5, SEQ ID NO.: 6, and SEQ ID NO.: 7, and the second VH region comprises three CDRs having amino acid sequences of SEQ ID NO.: 78, SEQ ID NO.: 79, and SEQ ID NO.: 80; and wherein in the fourth polypeptide, the third VH region comprises three CDRs having amino acid sequences of SEQ ID NO.: 5, SEQ ID NO.: 6, and SEQ ID NO.: 7, and the VL region comprises three CDRs having amino acid sequences of SEQ ID NO.: 82, SEQ ID NO.: 83, and SEQ ID NO.: 87.
Across independent claims, coverage is centered on an antibody binding molecule architecture consisting of two PD-L1-binding Fab regions and one CD3-binding Fv region, with the scope further defined by specific antibody light-chain CDR SEQ ID NO. identities and by defined VH and VL CDR SEQ ID NO. sets for the third and fourth polypeptides. Alternative independent coverage is provided by a second CDR set configuration for the relevant VH and VL regions.
Stated Advantages
The description states a stated rationale connected to monovalent Fv to reduce off-target T-cell activation.
Improved pharmacokinetics (PK) stability.
Documented Applications
Binding to Programmed Death-Ligand 1 (PD-L1) and Cluster of Differentiation 3 (CD3), including example target pairings described as PD-L1→CD3 and CD3 targeting in combination with other antigens (e.g., CD20→CD3, CD19→CD3, EGFR→CD3, Her2/TNFα).
Treating a disease or condition in a subject by administering a therapeutically effective amount of the binding molecule.
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