Combination of antibody-pyrrolobenzodiazepine derivative conjugate and PARP inhibitor
Inventors
HARADA, Naoya • KITAMURA, Michiko
Assignees
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Publication Number
US-12648946-B2
Publication Date
2026-06-09
Expiration Date
Abstract
A pharmaceutical composition for treatment of cancer or a method for treating cancer, wherein an antibody-pyrrolobenzodiazepine derivative conjugate and a PARP inhibitor are administered in combination.
Core Innovation
The invention is directed to a pharmaceutical composition for treatment of cancer that includes an antibody-pyrrolobenzodiazepine derivative conjugate together with a PARP inhibitor, administered in combination. The conjugate is defined by a structural formula in which Ab is an antibody or a functional fragment of the antibody, m1 is an integer of 1 or 2, and the N297 glycan is selected from N297-(Fuc)MSG1, N297-(Fuc)MSG2, a mixture thereof, and N297-(Fuc)SG.
The N297 glycan includes L(PEG), represented as a -(CH2CH2O)3-CH2CH2NH- segment, with the amino group bound via an amide bond to carboxylic acid at the 2-position of a sialic acid at the non-reducing terminal in branched chains of β-Man. Wavy lines represent bonding to Asn297 of the antibody, and the asterisk indicates bonding to a nitrogen atom at the 1- or 3-position of the triazole ring in the corresponding structural formula.
The method claims are directed to treating cancer that expresses CLDN6 and/or CLDN9 using the combination of the specified conjugate and a PARP inhibitor. The disclosure also refers to antibody formats that include functional fragments and antibody sequence constraints for antibodies that bind CLDN6/CLDN9, and frames the scope around a defined conjugate structure and combination therapy.
Claims Coverage
The claim set includes two independent claims. Across these, the inventive features focus on a structured antibody-pyrrolobenzodiazepine derivative conjugate defined by a specific N297 glycan structure and m1, and combination administration with a PARP inhibitor for cancer treatment, with one method claim further limited to cancers expressing CLDN6 and/or CLDN9.
Antibody-pyrrolobenzodiazepine derivative conjugate with defined N297 glycan structure
A conjugate having a formula wherein m1 is an integer of 1 or 2, Ab is an antibody or a functional fragment of the antibody, and the N297 glycan is N297-(Fuc)MSG1, N297-(Fuc)MSG2, a mixture thereof, and/or N297-(Fuc)SG, with wavy lines representing bonding to Asn297 and L(PEG) defined as -(CH2CH2O)3-CH2CH2NH- with bonding to the triazole ring indicated by an asterisk.
Combination administration with a PARP inhibitor for cancer treatment
A pharmaceutical composition for treatment of cancer wherein the antibody-pyrrolobenzodiazepine derivative conjugate and the PARP inhibitor are administered in combination.
Treatment of cancer expressing CLDN6 and/or CLDN9 using the conjugate/PARP inhibitor combination
A method for treating a cancer that expresses CLDN6 and/or CLDN9, wherein the antibody-pyrrolobenzodiazepine derivative conjugate and a PARP inhibitor are administered in combination, and the conjugate has the same defined formula with m1 and the specified N297 glycan variants.
Overall claim coverage centers on a cancer therapeutic combination: an antibody-pyrrolobenzodiazepine derivative conjugate with a specified Asn297-linked N297 glycan combined with PARP inhibition. One independent claim is directed to the composition, and the other further limits the method to cancers expressing CLDN6 and/or CLDN9.
Stated Advantages
Excellent antitumor effect is stated, including in PARP-insensitive cell lines/xenografts.
Superior cancer cell growth inhibition versus each agent alone is reported for pyrrolobenzodiazepine derivatives combined with PARP inhibitors, with lower IC50 values.
Improved tumor growth inhibition in vivo is reported when antibody-drug conjugates are combined with PARP inhibitors, with statistical significance reported.
Minor-groove DNA crosslinking is stated as not being involved through use of the specific PBD derivative.
Documented Applications
Treatment of cancer using an antibody-pyrrolobenzodiazepine derivative conjugate and a PARP inhibitor administered in combination.
Treatment of a cancer that expresses CLDN6 and/or CLDN9 using the same combination therapy.
Treatment and evaluation of cancer cell growth inhibition using pyrrolobenzodiazepine derivatives combined with PARP inhibitors, including olaparib, talazoparib, and talazoparib/niraparib.
In vivo antitumor evaluation in nude mice using antibody-drug conjugates combined with PARP inhibitors.
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