Protein recognizing drug moiety of antibody-drug conjugate
Inventors
SOMA, Masako • Kuga, Hiroshi • Masuda, Takeshi • KAWAMURA, Junko • ISHIBASHI, Hiromi • Yasuda, Satoru
Assignees
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Publication Number
US-12358999-B2
Publication Date
2025-07-15
Expiration Date
Abstract
A protein that recognizes a drug moiety of an antibody-drug conjugate in which a drug represented by the following formula is conjugated to an antibody via a linker, and a method for quantifying the concentration in plasma of an antibody-drug conjugate in a mammal to which the antibody-drug conjugate has been administered, by using the protein, and a method for identifying a tissue distribution of an antibody-drug conjugate.
Core Innovation
The invention provides a protein that recognizes a drug moiety of an antibody-drug conjugate in which a drug represented by a specified chemical formula is conjugated to an antibody via a linker. The recognizing protein is tied to an antibody component defined by heavy-chain and light-chain complementarity-determining regions represented by SEQ ID NOs, and the recognition is directed to the drug moiety within the ADC context.
In particular embodiments, the recognizing protein is an antibody with defined CDRH1, CDRH2, and CDRH3 in the heavy chain, and defined CDRL1, CDRL2, and CDRL3 in the light chain. The invention also includes an engineered antibody format in which a lysine residue at the carboxyl terminus of the heavy chain is deleted, together with specified heavy-chain and light-chain sequence residue ranges.
The invention further includes an antigen binding fragment recognizing the drug moiety, where the fragment is defined as Fab, F(ab')2, Fab', or Fv. The scope of the recognizing protein is tied to both the specified drug-linker/ADC drug-moiety formula and to particular antibody or antibody-fragment recognition elements defined through CDR sequences and engineered heavy-chain sequence modifications.
Claims Coverage
The independent claims are directed to three core concepts: a protein recognizing a drug moiety of an ADC via specified heavy- and light-chain CDR sequences, a protein recognizing the same ADC drug-moiety where the antibody has a deletion of a lysine residue at the carboxyl terminus of the heavy chain and defined sequence residue ranges, and a protein recognizing the ADC drug-moiety where the protein is an antigen binding fragment with specified CDR sets and fragment format.
Protein recognizing a drug moiety of an ADC defined by CDR sequences
A protein that recognizes a drug moiety of an antibody-drug conjugate in which a drug represented by a specified chemical formula is conjugated to an antibody via a linker, wherein the protein is an antibody comprising heavy-chain CDRH1, CDRH2, CDRH3 and light-chain CDRL1, CDRL2, CDRL3 defined by SEQ ID NOs, including alternative CDR sets.
Engineered antibody with carboxyl-terminus heavy-chain lysine deletion for drug-moiety recognition
A protein that recognizes a drug moiety of an antibody-drug conjugate with a specified drug chemical formula conjugated to an antibody via a linker, wherein the protein is an antibody in which a lysine residue at the carboxyl terminus of the heavy chain is deleted, and the antibody comprises heavy-chain and light-chain amino-acid sequence segments defined by residue ranges from specified SEQ ID NOs.
Antigen binding fragment recognizing the ADC drug moiety via CDR sequences
A protein that recognizes a drug moiety of an antibody-drug conjugate with a specified drug chemical formula conjugated to an antibody via a linker, wherein the protein is an antigen binding fragment of an antibody defined by CDRH1, CDRH2, CDRH3, and CDRL1, CDRL2, CDRL3 sequence definitions by SEQ ID NOs, and limited to Fab, F(ab')2, Fab', or Fv formats.
Across the independent claims, the patent coverage centers on a protein whose recognition is directed to a drug moiety of an ADC defined by a chemical formula, with recognition specified by defined antibody CDR sequence elements. Claim coverage also includes a protein limited to an engineered heavy-chain deletion variant and an ADC-drug-moiety recognizing antigen binding fragment limited to specific fragment types.
Stated Advantages
The released drug compound (2) has confirmed topoisomerase I inhibitory activity.
The invention protein recognizes the released drugs and/or ADC drug moieties.
Recognition can be substantially independent of DAR differences.
Enables plasma quantification.
Enables tissue distribution determination.
Documented Applications
Use of downstream protein measurement and analysis in immunoassays including ELISA, ECL, and immunohistochemistry (IHC), with antigen and positive/negative control compound discussion.
Measurement/assessment use cases including quantifying or identifying antibody-drug conjugate/drug levels and distributions in a mammal.
A kit for quantifying, in mammal plasma, the concentration of an antibody-drug conjugate and/or a drug released from that antibody-drug conjugate after administration.
Quantifying, in mammal plasma, the concentration of an antibody-drug conjugate and/or a drug released from that antibody-drug conjugate after administration.
Non-clinical plasma concentration assay development for the mouse antibody 1A3, with reported mean plasma concentrations in contexts described for HER2-ADC (I), HER3-ADC (I), TROP2-ADC (I), and B7-H3-ADC (I).
Immunostaining and specificity/competition experiments using 1A3 and rabbit chimeric 1A3 with ADC-treated tumors and chemical competitors including compound (2) and SN-38.
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