Antibody-drug conjugates and uses thereof
Inventors
Chuang, Shih-Hsien • CHAO, Wei-Ting • Sun, Wei-Ting • Hsu, Hui-Jan • Lin, Wun-Huei
Assignees
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Publication Number
US-11384150-B2
Publication Date
2022-07-12
Expiration Date
Abstract
An immunoconjugate, comprising an anti-EGFR antibody or a binding fragment thereof, and a kinase inhibitor.
Core Innovation
The invention relates to anti-EGFR antibody-kinase inhibitor immunoconjugates having an immunoconjugate formula Ab-(L-D)m, where Ab is cetuximab and m is an integer of 1-20. The immunoconjugate comprises an anti-EGFR antibody or a binding fragment thereof and a kinase inhibitor, with SRC-kinase inhibition referenced and staurosporine or dasatinib cited as inhibitor examples within the immunoconjugate constructs.
The disclosed immunoconjugates include an anti-EGFR antibody, including cetuximab, or a binding fragment thereof, conjugated to a kinase inhibitor. The immunoconjugates are presented in structural and compositional embodiments where the antibody is linked to the kinase inhibitor payload through defined linker parameters, including a thioether bond and linker structural options using Z (NH or S).
The patent states that the antibody + kinase inhibitor immunoconjugate is more effective than antibody alone or combination in certain mutation contexts. The disclosure situates the immunoconjugates for cancers resistant to an anti-EGFR antibody or resistant to an EGFR tyrosine kinase inhibitor, and it references KRAS, BRAF, PIK3CA, PTEN, EGFR, P53, and SRC in the mutation context.
Claims Coverage
The independent claim covers an immunoconjugate defined by a specific formula that combines an anti-EGFR antibody or binding fragment with a kinase inhibitor, with Ab identified as cetuximab and m as an integer from 1 to 20. The dependent claims refine the quantitative parameter m, add pharmaceutical composition coverage with a pharmaceutically acceptable carrier, and define cancer-treatment methods including subject selection based on resistance to anti-EGFR modalities and optional determination of whether the cancer has a mutation prior to administering treatment.
Immunoconjugate defined by Ab-(L-D)m with cetuximab and m=1-20
An immunoconjugate comprising an anti-EGFR antibody or a binding fragment thereof and a kinase inhibitor, wherein the immunoconjugate has the formula Ab-(L-D)m, wherein Ab is cetuximab and m is an integer of 1-20.
Immunoconjugate with m constrained to 2-8
The immunoconjugate of claim 1 wherein m is within the range of 2 to 8.
Pharmaceutical composition including immunoconjugate and pharmaceutically acceptable carrier
A pharmaceutical composition including the immunoconjugate of claim 1 and a pharmaceutically acceptable carrier.
Cancer treatment method administering an effective amount
Treating cancer in a subject by administering an effective amount of the immunoconjugate described in claim 1.
Treatment for cancers resistant to anti-EGFR antibody or EGFR tyrosine kinase inhibitor
The method includes a subject whose cancer is resistant to an anti-EGFR antibody or binding fragment, or to an EGFR tyrosine kinase inhibitor.
Pre-treatment determination whether the cancer has a mutation
The method further includes, before administering a treatment, determining whether the cancer has a mutation.
Overall, the claims concentrate on an anti-EGFR antibody-kinase inhibitor immunoconjugate characterized by Ab-(L-D)m with Ab=cetuximab and m=1-20, refined by m ranges and by formulation into a pharmaceutical composition. The method claims cover cancer treatment by administering an effective amount, with additional selection for anti-EGFR resistant cancers and optional determination of whether the cancer has a mutation prior to treatment.
Stated Advantages
The antibody + kinase inhibitor immunoconjugate is unexpectedly discovered to be more effective than antibody alone or combination in certain mutation contexts.
Documented Applications
Cancer inhibition and cancer treatment by administering the immunoconjugate to a subject.
Treatment of cancers resistant to an anti-EGFR antibody or binding fragment, or resistant to an EGFR tyrosine kinase inhibitor.
Use where, prior to administering treatment, it is determined whether the cancer has a mutation.
Efficacy trends in KRAS/BRAF mutation-defined colon cancer cell lines (SW48, HT-29, SW480), including comparison of antibody-drug conjugate activity versus cetuximab alone or cetuximab + free staurosporine.
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