Duocarmycin ADCs for use in treatment of endometrial cancer
Inventors
SANTIN, Alessandro Davide • GOEDINGS, Peter Johannes
Assignees
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Publication Number
US-10092659-B2
Publication Date
2018-10-09
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
The invention provides a method of treating endometrial cancer expressing HER2 in a human patient by administering a therapeutically effective amount of a compound of formula (I). The compound includes an anti-HER2 antibody or an anti-HER2 antibody fragment able to bind HER2, with n selected from 0, 1, 2, or 3 and an average DAR (m) from 1 to 4, and R1 and R2 selected from specified groups.
The disclosed compound is associated with duocarmycin-containing HER2-targeting ADCs, including cysteine-linked anti-HER2 antibodies, with formula (I)/(II) described using average DAR and structural substituent group selections. The document further constrains aspects of the ADC structure through ranges for n and average DAR and specifies substituent groups R1 and R2 within the formula.
The document addresses limited efficacy of HER2-targeting therapies in biomarker-defined tumors and an unexpected lack of efficacy of trastuzumab and T-DM1 in the described target setting. It characterizes a duocarmycin mechanism as DNA-alkylating and provides comparisons using SYD985 versus T-DM1 in relevant in vitro and in vivo xenograft settings.
Claims Coverage
The independent claims cover methods of treating HER2-expressing endometrial cancer by administering therapeutically effective amounts of duocarmycin-containing HER2-targeting ADC compounds defined by specific structural and parameter constraints, with the primary quantitative inventive focus being n (0–3) and average DAR ranges (1–4, and specifically 2.5–2.9).
HER2-targeted ADC compound of formula (I) with n and average DAR constraints
Administering a therapeutically effective amount of a compound of formula (I) to treat endometrial cancer expressing HER2, where the anti-HER2 antibody or fragment binds HER2; n is 0, 1, 2, or 3; m is an average DAR from 1 to 4; and R1, y, and R2 are selected from specified groups.
Defined average DAR compound structure with 2.5–2.9 average DAR range
Administering a therapeutically effective amount of a compound having a specified structure to treat endometrial cancer expressing HER2, where 2.5–2.9 represents the average DAR for the compound.
Overall, claim coverage focuses on administering defined HER2-targeting ADC compounds to treat HER2-expressing endometrial cancer, with inventive scope centered on specified antibody-binding components and quantitative average DAR, including 1–4 and particularly 2.5–2.9.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating endometrial cancer expressing HER2 in a human patient, including uterine serous carcinoma, particularly with moderate/low HER2 expression (IHC 2+ or 1+) and/or HER2 FISH-negative status.
Evaluating duocarmycin-containing HER2-targeting ADCs in in vitro cytotoxicity and in vivo xenograft settings, comparing SYD985 versus T-DM1.
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