Bioconjugates containing sulfamide linkers for use in treatment
Inventors
Verkade, Jorge Merijn Mathieu • Wijdeven, Maria Antonia • VAN DE SANDE, Petrus Josephus Jacobus Maria • Van Geel, Remon • van Delft, Floris Louis • Van Berkel, Sander Sebastiaan
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11951175-B2
Publication Date
2024-04-09
Expiration Date
Abstract
The present invention is based on the surprising finding that the linker employed in a bioconjugate, such as an anti-body-drug conjugate, is not therapeutically inert but has an effect on the therapeutic index of the bioconjugate. The present invention thus concerns a method for increasing the therapeutic index of a bioconjugate and the bioconjugates for use in treatment, in particular cancer. The bioconjugates according to the invention have a sulfamide linker comprising a group according to formula (1).
Core Innovation
The invention concerns increasing the therapeutic index of a bioconjugate by preparing an antibody-based bioconjugate of formula (A): B-Z3-L-(D), where B is an antibody, L is a linker linking Z3 and D, and z is 1, 2, 3 or 4. Z3 is a connecting group obtained by reacting a reactive group Q1 on a linker-conjugate having formula Q1-L-D with a functional group F1 on the antibody, and Z3 is connected to B through a glycan on the antibody.
The linker architecture is defined by formula (8a) or (8b), or a salt thereof, with spacer moieties Sp1, Sp2, Sp3 and Sp4 and connecting groups Z1 and Z2 in the overall linker framework. The disclosed structural variants include parameter constraints on a, b, c, d, e, f, g and i, together with defined R1 options, and the connecting-group formation uses a selected conjugation reaction between Q1 and F1, including cycloaddition and other described conjugation modalities.
The invention is explicitly associated with therapeutic index enhancement, including improved efficacy and tolerability, and is described in a treatment context that preferably relates to cancer. The disclosure further states that the linker design improves conjugation efficiency versus PEG, increases polarity and solubility before, during and after conjugation, and is suitable for hydrophobic target compounds with reduced cosolvent and aggregation.
Claims Coverage
The consolidated claim coverage includes two independent claims. Both center on a glycan-mediated antibody bioconjugate architecture for therapeutic-index enhancement, and one further claim covers administering the defined bioconjugate to a subject; in total, the independent claims emphasize one core inventive feature set with related linker and conjugation refinements.
Glycan-mediated antibody connecting group and reactive group coupling architecture
Z3 is a connecting group obtained by reacting a reactive group Q1 on a linker-conjugate having a formula Q1-L-D with a functional group F1 on the antibody, wherein Z3 is connected to B through a glycan on the antibody; each occurrence of "—" is independently a bond or a spacer moiety.
Defined antibody bioconjugate of formula (A) with linker formula (8a) or (8b)
Preparing the bioconjugate of formula (A): B-Z3-L-(D), wherein B is an antibody, L is a linker linking Z3 and D, D is a target molecule, z is 1, 2, 3 or 4, and L is formula (8a) or (8b) or a salt thereof, with defined spacer moieties Sp1, Sp2, Sp3 and Sp4 and connecting groups Z1 and Z2.
Selected linker substructures with parameter constraints
L is represented by formula (8a) or (8b), or a salt thereof, with a, b, c, d, e, g and i defined as 0 or 1, f an integer in the range of 1 to 10, at least one of b, e and i not 0, at least one of g, d and c not 0, and R1 selected as defined.
Treatment administration of the defined bioconjugate to increase therapeutic index
Administering to a subject a bioconjugate represented by formula (A) wherein B is an antibody, L is a linker linking Z3 and D, Z3 is obtained by reacting a reactive group Q1 on a linker-conjugate with a functional group F1 on the antibody through a glycan, z is 1, 2, 3 or 4, and L is formula (8a) or (8b) or a salt thereof.
The independent claims are centered on a glycan-mediated antibody bioconjugate defined by B-Z3-L-(D), with Z3 formed from reactive group Q1 and antibody functional group F1 and with L defined by formula (8a) or (8b) or a salt thereof. One independent claim further recites administering the resulting bioconjugate to a subject, while the broader claim coverage also includes defined linker parameters, spacer moieties, connecting groups, and selected conjugation reactions.
Stated Advantages
Increase therapeutic index of the bioconjugate.
Increase therapeutic index expressed as higher TD50/ED50.
Provide a wider therapeutic window enabling lower dosing or altered frequency.
Improve efficacy and tolerability.
Improve conjugation efficiency versus PEG.
Increase polarity and improve solubility before, during and after conjugation.
Suitability for hydrophobic target compounds with reduced cosolvent and aggregation.
Ease of synthesis and high yields.
Documented Applications
A method of treatment comprising administering to a subject the antibody bioconjugate of formula (A), including a dependent treatment use for cancer.
Bioconjugates including antibody-drug conjugates (ADCs) for treatment of subjects, including in cancer contexts.
Interested in licensing this patent?