Antibodies directed to claudin 6, including bispecific formats thereof
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Publication Number
US-12049502-B2
Publication Date
2024-07-30
Expiration Date
Abstract
The disclosure is directed to an antibody specific for claudin 6 and CD3 and method of preparing and using the same. The present disclosure describes the isolation and characterization of antibodies, antibody fragments, and antibody variants specific for claudin 6 and CD3.
Core Innovation
The invention provides bispecific antibodies that bind to claudin 6 (CLDN6) and CD3. The bispecific antibody comprises polypeptides configured with defined variable light chain regions and defined variable heavy chain regions, including CDR1, CDR2, and CDR3 sequences specified by amino acid sequences referenced to SEQ ID NOs 1, 2, and 3 for a first light chain, and SEQ ID NOs 4, 5, and 6 for a first variable heavy chain region.
In additional embodiments, the bispecific antibody further includes a second set of variable regions and constant-domain features across the second and third polypeptides. The variable-region definitions include CDR sequences and, in certain embodiments, at least 95% identical amino acid sequences relative to reference sequences such as SEQ ID NO: 67, SEQ ID NO: 79, and SEQ ID NO: 89. The polypeptide architectures therefore specify defined binding agents through named sequence region constraints.
The invention also includes constant-domain mutation combinations, including Fc constant-domain mutations described with EU numbering in human IgG1. Specific Fc/constant-domain mutation sets include combinations such as T366W, T366S, T366Y, Y407V, Y407T, F405A, T394W, D399C, K392C, S354C, Y349C, E356C, and E357C, with optional LALA mutations (L234A/L235A). The described Fc mutations are reported in the context of increasing specificity for FcγRIIA.
Claims Coverage
The independent claims cover three alternative ways of defining the CLDN6:CD3 bispecific antibody: (i) a three-polypeptide construct with explicitly defined CDR sequences, (ii) a three-polypeptide construct with CDR sequences plus at-least-95% identity constraints to specified SEQ ID references, and (iii) a construct defined solely by three specified polypeptide amino-acid sequences.
Claudin 6 (CLDN6) and CD3 bispecific antibody defined by specified CDR sequences across three polypeptides
A bispecific antibody that binds CLDN6 and CD3, comprising a first polypeptide with a first variable light chain region having CDR1, CDR2, and CDR3 sequences defined by SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3; a second polypeptide with a first variable heavy chain region having CDR1, CDR2, and CDR3 sequences defined by SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6; and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89.
Claudin 6 (CLDN6) and CD3 bispecific antibody with specified CDR sequences and at least 95% identical variable-region sequences
A bispecific antibody that binds CLDN6 and CD3 comprising: a first polypeptide with a first variable light chain region having CDR1, CDR2, and CDR3 sequences defined by SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 and an at least 95% identical amino acid sequence to SEQ ID NO: 67; a second polypeptide with a first variable heavy chain region having CDR1, CDR2, and CDR3 sequences defined by SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6; and a third polypeptide including a second variable heavy chain region with CDR1, CDR2, and CDR3 sequences defined by SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27 and a second variable light chain region with CDR1, CDR2, and CDR3 sequences defined by SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30 (or a variant thereof), wherein the second polypeptide comprises an amino acid sequence at least 95% identical to SEQ ID NO: 79 and the third polypeptide comprises an amino acid sequence at least 95% identical to SEQ ID NO: 89.
Claudin 6 (CLDN6) and CD3 bispecific antibody defined by three specified polypeptide sequences
A bispecific antibody comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 67, a second polypeptide comprising the amino acid sequence of SEQ ID NO: 79, and a third polypeptide comprising the amino acid sequence of SEQ ID NO: 89.
Across the independent claims, the claim coverage centers on CLDN6:CD3 bispecific antibodies defined by specified variable-region CDR sequences and/or specified amino-acid sequences for polypeptides, with the second independent claim additionally anchored by at-least-95% sequence identity constraints. Dependent claims refine these constructs with constant-domain/Fc mutation sets and with inclusion in pharmaceutical compositions containing pharmaceutically acceptable excipients.
Stated Advantages
Stated binding/affinity of CLDN6, including a CLDN6 binding level stated as <10 nM and higher affinity versus CLDN3/4/9.
The described Fc mutations can increase specificity for FcγRIIA.
Documented Applications
Cancer treatment using CLDN6/CD3 targeting and modulation through the disclosed bispecific antibodies.
Modulating CLDN6/CD3.
Treating or preventing cancer across many cancer types.
Addressing cytokine release syndrome (CRS) and toxicity considerations in the context of cancer treatment.
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