Antibody-drug conjugates containing an anti-mesothelin antibody and uses thereof
Inventors
Chuang, Shih-Hsien • Sun, Wei-Ting • LAILEE, YING-SHUAN • Lai, Chun-Liang • Lin, Wun-Huei • Wei, Win-Yin • Tsai, Shih-Chong • YU, CHENG-CHOU • Huang, Chao-Yang
Assignees
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Publication Number
US-11998613-B2
Publication Date
2024-06-04
Expiration Date
Abstract
The present disclosure provides an immunoconjugate includes an antibody comprising an antigen-binding fragment that specifically binds to an epitope in mesothelin, N-glycan binding domain and an N-glycan; a linker linking to the N-glycan; and a payload A and a payload B conjugated to the linker, respectively; wherein the payload A and the payload B are the same or different. A pharmaceutical composition comprises the immunoconjugate and a method for treating cancer are also provided in the disclosure.
Core Innovation
The invention relates to an immunoconjugate comprising an antibody that specifically binds to an epitope in mesothelin, an N-glycan binding domain, and an N-glycan having a structure of formula (1). The N-glycan presents "*" as a bond or a protecting group, and a linker links to each "*" when "*" presents the bond.
The immunoconjugate includes payload A and payload B independently conjugated to the linkers, wherein the payload A and the payload B are the same or different. The antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 11 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 12.
The document also describes antibody conjugates assembled from azide-functionalized anti-MSLN antibodies and DBCO-linked linker-payload constructs. Example embodiments include payloads such as MMAE, DM1, seco-DUBA, exatecan, and Dxd2, with variants containing PEG and peptide GGFG components and different DBCO-linked forms.
Claims Coverage
The independent claim coverage centers on an immunoconjugate architecture with mesothelin epitope binding, an N-glycan binding domain, a defined N-glycan structure of formula (1), and independently conjugated payloads A and B. Across the independent claim features, there are four inventive features.
Mesothelin-targeting N-glycan-binding immunoconjugate with defined N-glycan structure
An antibody comprising an antigen-binding fragment that specifically binds to an epitope in mesothelin, an N-glycan binding domain and an N-glycan having a structure of formula (1).
N-glycan-linked conjugation via linkers to bond/protecting group sites
A linker linking to each of the "*" in the N-glycan when "*" presents the bond, wherein "*" represents a bond or a protecting group.
Dual payload conjugation through independently conjugated payloads A and B
A payload A and a payload B independently conjugated to the linkers, wherein the payload A and the payload B are the same or different.
Specified antibody variable-region sequences
The antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 11, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 12.
Overall, the claim coverage is anchored by mesothelin epitope binding, an N-glycan binding domain with an N-glycan of formula (1), linker attachment at N-glycan "*" bond or protecting group positions, independently conjugated payloads A and B, and specified heavy- and light-chain variable region sequences.
Stated Advantages
More stable conjugation versus random conjugation.
Improved efficacy in a xenograft model.
Documented Applications
In vitro cytotoxicity evaluation and internalization assay evaluation of ADC constructs.
In vivo pharmacokinetic evaluation in mice/rats.
Xenograft efficacy studies in pancreatic and ovarian cancer models using tumor growth inhibition comparisons between ADC constructs and payload controls, with body weight observations.
Use in a method of treating cancer, including mesothelin-expressing cancers.
Therapeutic-agent payload embodiments and label payload embodiments are described for the immunoconjugate.
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