Anti-HER3 antibody-drug conjugate
Inventors
Hettmann, Thore • Abraham, Reimar • BLUM, Sabine • UENO, Suguru
Assignees
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Publication Number
US-12685781-B2
Publication Date
2026-07-21
Expiration Date
Abstract
To provide an antitumor drug having excellent therapeutic effect, which is excellent in terms of antitumor effect and safety. Provided is an antibody-drug conjugate in which an antitumor compound represented by the following formula is conjugated to an anti-HER3 antibody via a linker having a structure represented by the formula: -L1-L2-LP-NH—(CH2)n1-La-(CH2)n2-C(═O)— or -L1-L2-LP- (the anti-HER3 antibody is connected to the terminal of L1, the antitumor compound is connected to the carbonyl group of —(CH2)n2-C(═O)— moiety or the C terminal of LP, with the nitrogen atom of the amino group at position 1 as a connecting position).
Core Innovation
The patent describes an antibody-drug conjugate in which a linker and an antitumor compound are connected to an anti-HER3 antibody at position 3. The antitumor compound is represented by specified formulae, including structures corresponding to SEQ ID NO:585 and SEQ ID NO:590, and includes a (Succinimid-3-yl-N) moiety connected to the antibody at position 3 and a (NH-DX) moiety connected through the nitrogen atom of an amino group at position 1.
The linker architecture includes GGFG, DGGFG, and related variants, with defined linker-building components such as -L1-L2-LP- linker structures and related connectivity between the antibody, linker, and antitumor compound. The document also describes exatecan as the antitumor payload and includes maleimidyl-containing intermediates and thioether-forming conjugation chemistry at the antibody hinge position 3.
The disclosure further centers the anti-HER3 antibody component on specific heavy and light chain sequence identifiers and CDRH/CDRL region sourcing from named antibodies such as U1-49, U1-53, U1-59, U1-7, and U1-9. It also provides examples of antibody-drug conjugates with reported average drug-linker loading, and identifies intended anticancer therapeutic and prophylactic use against HER3-expressing cancers.
Claims Coverage
The combined claim coverage centers on one independent anti-HER3 antibody-drug conjugate claim defining a linker and antitumor compound connected to the antibody at position 3. Across the provided items, the dependent claims refine this core by specifying an average drug-linker loading range, antibody heavy and light chain sequence identities, absence of a heavy-chain carboxyl-terminus lysine residue, CDR sourcing from named antibodies, and salt or formulation embodiments.
Position-3 anti-HER3 antibody-drug conjugate with defined linker and antitumor compound
An antibody-drug conjugate wherein a linker and an antitumor compound represented by specified formulae are connected to an anti-HER3 antibody at position 3, including the (Succinimid-3-yl-N) structure connected to the antibody at position 3 and the (NH-DX) group connected through the nitrogen atom of an amino group at position 1.
Average drug-linker unit loading
An average of 2 to 8 drug-linker structure units are conjugated per antibody.
Specific heavy and light chain sequences
The antibody-drug conjugate contains heavy and light chain amino acid sequences of SEQ ID Nos: 583 and 584, respectively.
Absence of a heavy-chain carboxyl-terminus lysine residue
The heavy chain of SEQ ID NO: 583 lacks the lysine residue at the carboxyl terminus.
CDR regions from named antibodies
The antibody comprises specified CDRH1–CDRH3 and CDRL1–CDRL3 regions from one of the listed antibodies U1-49, U1-53, U1-59, U1-7 or U1-9 in the heavy and light chains, respectively.
Drug formulation and salt form
A drug formulation containing the antibody-drug conjugate of claim 1 or a salt form of the drug.
Overall, the claims define an anti-HER3 antibody-drug conjugate with specified linker and antitumor compound formulae at antibody position 3, and further narrow the scope by sequence-defined antibody features, CDR sourcing from named antibodies, loading constraints, and formulation or salt coverage.
Stated Advantages
HER3 binding is not significantly impaired by conjugation.
ADC functional activity includes HER3 signal inhibition/internalization and in vitro growth/survival inhibition.
Stronger antitumor activity is associated with higher drug loadings.
HER3-dependent effects are demonstrated in vivo using U1-59 pre-dosing.
Combination potentiation is described with agents including trastuzumab, gefitinib, cetuximab/panitumumab, and other agents listed in the document.
Potentiates antitumor effects when combined with standard targeted agents in multiple tumor models.
No weight loss was observed in treated groups.
No serious toxicity findings were reported in rats and monkeys at up to 30 mg/kg within observation windows.
Improved antitumor effect using the specific anti-HER3 linker-exatecan antibody-drug conjugate.
Improved safety using the specified linker-exatecan conjugate on an anti-HER3 antibody.
Reported in vitro and in vivo antitumor activity for the example antibody-drug conjugates (1)-(7).
Documented Applications
In vitro testing of HER3 binding and functional activity of pooled/filtered antibody-drug conjugate mixtures.
In vitro ATP-based growth/survival inhibition across cancer cell lines in the described evaluations.
In vivo antitumor efficacy comparisons in xenograft mouse models including HER3-dependent effects via U1-59 pre-dosing.
Combination therapy evaluations described with agents including trastuzumab, gefitinib, and cetuximab/panitumumab and other agents listed in the document.
Use in patient-derived tumor models is described in the document.
In vivo xenograft experiments in nude mice using an anti-HER3 antibody-drug conjugate combined with trastuzumab in PIK3CA H1047R trastuzumab-resistant breast cancer models, including trastuzumab/pertuzumab resistance models.
In vivo xenograft experiments in nude mice using an anti-HER3 antibody-drug conjugate combined with gefitinib in PC-9 lung cancer models.
In vivo xenograft experiments in nude mice using an anti-HER3 antibody-drug conjugate combined with cetuximab or panitumumab in triple-negative breast cancer models and in head/neck cancer.
Therapeutic and prophylactic use against HER3-expressing cancers.
Anti-breast, anti-lung, and anti-melanoma activity statements for in vitro and in vivo comparisons.
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