Duocarmycin ADCs for use in treatment of endometrial cancer
Inventors
SANTIN, Alessandro Davide • GOEDINGS, Peter Johannes
Assignees
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Publication Number
US-9427480-B2
Publication Date
2016-08-30
Expiration Date
Abstract
The present invention relates to duocarmycin-containing antibody-drug conjugates (ADCs) for use in the treatment of human solid tumors expressing HER2, wherein the human solid tumor expressing HER2 is endometrial cancer, in particular uterine serous carcinoma (USC). In particular, the present invention relates to duocarmycin-containing ADCs for use in the treatment of endometrial cancer, notably USC, with HER2 IHC 2− or 1+ and HER2 FISH negative tumor tissue status.
Core Innovation
Duocarmycin-containing HER2-targeting antibody-drug conjugates (ADCs), including trastuzumab- and anti-HER2-Ab based variants such as SYD985, are disclosed for treating endometrial cancer, with emphasis on uterine serous carcinoma (USC). The disclosure relates to tumors with moderate/low HER2 expression (IHC 2+ or 1+) and/or tumors without HER2 gene amplification (FISH negative).
A compound of formula (I) is defined that comprises a cysteine-linked anti-HER2 antibody fragment/antibody and a duocarmycin drug component. The disclosure describes varying parameters including n (0-3), m as an average DAR (average drug-to-antibody ratio) with embodiments having preferred DAR ranges 2-3 and 2.5-2.9, and choices for substituents R1/R2 as illustrated by structures.
The disclosure argues unexpected efficacy versus comparator trastuzumab and T-DM1 (ado-trastuzumab emtansine) in targeted HER2 IHC 1+/2+ and FISH-negative settings. The testing context includes in vitro and in vivo evaluation, including USC cell line cytotoxicity and xenograft efficacy in SCID mice, with SYD985 described as substantially more potent than T-DM1 in primary USC cell lines.
Claims Coverage
The independent claim is directed to a method for treating uterine serous carcinoma expressing HER2 in a human patient, with a specified compound structure and an average DAR requirement (2.5-2.9), resulting in one main claimed inventive setup plus dependent claim refinements (not fully extracted from the partial content beyond the summarized dependents).
Treatment of uterine serous carcinoma expressing HER2 with an ADC having an average DAR of 2.5-2.9
A method of treating uterine serous carcinoma expressing HER2 in a human patient by administering a therapeutically effective amount of a compound having the structure, wherein 2.5-2.9 represents an average DAR for the compound.
Overall, the claim coverage centers on administering a therapeutically effective amount of an anti-HER2 duocarmycin ADC compound defined by formula (I), with the key inventive constraint being the compound’s average DAR in the range 2.5-2.9 for treating uterine serous carcinoma expressing HER2.
Stated Advantages
Unexpected efficacy versus comparator trastuzumab and T-DM1 in targeted HER2 IHC 1+/2+ and FISH-negative settings.
Substantially more potent than T-DM1 in primary USC cell lines.
Documented Applications
Treating uterine serous carcinoma (USC) in a human patient, including cases characterized by moderate/low HER2 expression (IHC 2+ or 1+) and/or absence of HER2 gene amplification (FISH negative).
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