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Publication Number
US-10633458-B2
Publication Date
2020-04-28
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 relates to ALiCE cell-engaging antibody-like binding molecules for cancer immunotherapy that include multiple antibody polypeptides arranged to form first and second antigen binding Fab regions and an antigen binding Fv region. The first Fab region and the second Fab region bind Cluster of Differentiation 20 (CD20), while the Fv region binds Cluster of Differentiation 3 (CD3), and the Fab regions and the Fv region are organized from N-terminus to C-terminus using antibody light chain, VH, CH1, and VL segments.
The binding molecules are defined by complementarity determining regions (CDRs) referenced by SEQ ID NOs. The antibody light chains each comprise three CDRs having amino acid sequences of SEQ ID NO.: 31, SEQ ID NO.: 32, and SEQ ID NO.: 33, and the VH and VL components include CDRs with specified amino acid sequences referenced by SEQ ID NO.: 27, SEQ ID NO.: 28, SEQ ID NO.: 29 and SEQ ID NO.: 17, SEQ ID NO.: 18, SEQ ID NO.: 19.
The patent further describes engineered ALiCE binding molecules designated ACE-04 through ACE-12 and mentions ACE-09 through ACE-11 variants. It reports assembly and expression characterization, including evaluation of linker-length effects using G4S linker variants, with observations including proper assembly and comparable expression levels across different linker lengths.
Claims Coverage
The independent claims cover a CD20/CD3 binding molecule with a defined multi-polypeptide Fab/Fv architecture and specified CDR sequences, a method of making that binding molecule by expressing and purifying it, and a pharmaceutical composition comprising the binding molecule in a pharmaceutically acceptable carrier. Across the independent claims, the architecture includes four polypeptides that assemble into two antigen binding Fab regions and a CD20/CD3-directed Fv region, with multiple CDRs specified by SEQ ID NOs.
Multi-polypeptide Fab/Fv CD20-CD3 binding architecture
A binding molecule comprising a first polypeptide and a second polypeptide each comprising an antibody light chain; a third polypeptide comprising an ordered first VH region and first CH1 region and a second VH region; and a fourth polypeptide comprising an ordered third VH region and second CH1 region and a VL region, where the first Fab region and second Fab region form from the specified VH/CH1/light-chain components and where the second VH region and VL region form an antigen binding Fv region.
CD20 and CD3 binding specificity via defined Fab and Fv regions
The first Fab region and the second Fab region bind Cluster of Differentiation 20 (CD20), and the Fv region binds Cluster of Differentiation 3 (CD3).
Specified antibody CDR sequences for light chain, VH, and VL regions
The antibody light chains each comprise three CDRs having amino acid sequences of SEQ ID NO.: 31, SEQ ID NO.: 32, and SEQ ID NO.: 33, and the VH and VL regions include three CDRs each having amino acid sequences of the specified SEQ ID NOs., including the sets (SEQ ID NO.: 27, SEQ ID NO.: 28, and SEQ ID NO.: 29) and (SEQ ID NO.: 17, SEQ ID NO.: 18, and SEQ ID NO.: 19) as defined for the respective regions.
Expression in a host cell from vectors and purification
A method of making a binding molecule comprising expressing the binding molecule from one or more vectors in a host cell, wherein the vectors encode the first and second antibody light-chain polypeptides and the third and fourth polypeptides containing the ordered VH/CH1/VL regions to form the Fab and Fv regions, followed by purifying the binding molecule.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising the binding molecule and a pharmaceutically acceptable carrier, wherein the binding molecule comprises the multi-polypeptide Fab/Fv architecture and CD20/CD3 binding specificity defined in the claim.
Collectively, the independent claims require a binding molecule built from multiple antibody polypeptides that assemble into two Fab regions binding CD20 and an Fv region binding CD3, with defined CDR amino acid sequences specified by SEQ ID NOs. The claims also cover making the molecule by expressing the polypeptides from vectors in a host cell and purifying it, and include use of the molecule in a pharmaceutical composition with a pharmaceutically acceptable carrier.
Stated Advantages
Reduced undesirable Fc-mediated cytotoxicity.
Improved heterodimerization stability.
Improved half-life via optional albumin-binding sites (ABS).
Documented Applications
Cancer immunotherapy using ALiCE cell-engaging antibody-like binding molecules.
T cell redirecting assay (assay type described).
Cytotoxicity assay (assay type described).
Pharmacokinetic (PK) studies (study type described).
Xenograft study (study type described).
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