Compounds and therapeutics uses thereof
Inventors
WESTBY, Michael • GLOSSOP, Melanie • WATSON, Christine • PICKFORD, Christopher
Assignees
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Publication Number
US-11766483-B2
Publication Date
2023-09-26
Expiration Date
Abstract
The invention relates to novel compounds with the ability to link an immune response to a defined therapeutic target, to the use of said compounds in treating cancer and infectious diseases, to compositions containing said compounds, processes for their preparation and to novel intermediates used in said process.
Core Innovation
The invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein L represents an antibody or antigen binding fragment thereof, X1 represents an antibody or antigen binding fragment attachment moiety, and F represents a carbohydrate molecule capable of binding to a human anti-alpha-galactosyl antibody. The compound includes defined spacer/linker motifs S1 and S2 and an aryl core Cy selected from phenyl, biphenyl, or triphenyl.
The structure is defined by specific integer ranges and by Y1 and Y2 bond types selected from the listed linkage groups, thereby specifying the connectivity between the carbohydrate-binding element and the antibody-binding element. When Cy is biphenyl or triphenyl, the [F-S2-Y2]m group or groups and the -Y1-S1-X1-L group may be present on any of said phenyl rings.
The document also describes preparation of compounds of formula (I) through reaction of thiol- or amino-containing antibody or antigen binding fragments with formula (II) derivatives to form intermediates of formulas IA, IC, and TB, with possible interconversion among formula (I) species or protected derivatives. Disclosed examples and analytical characterization include antibody constructs built around cetuximab/cetuximab-Fab and rituximab/rituximab Fab.
Claims Coverage
The provided claims cover two inventive features: a defined compound of formula (I) and a preparation process for that compound. The compound claim centers on the antibody or antigen binding fragment moiety, the S1 and S2 spacer/linker motifs, the carbohydrate molecule F capable of binding to a human anti-alpha-galactosyl antibody, and the aryl core Cy.
Antibody-linked carbohydrate compound of formula (I)
A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein L is an antibody or an antigen binding fragment thereof; S1 and S2 are defined spacer groups with optional substitutions; X1 is an antibody or antigen binding fragment attachment moiety; F is a carbohydrate molecule capable of binding to a human anti-alpha-galactosyl antibody; and Cy is phenyl, biphenyl, or triphenyl with specified ring attachment possibilities.
Preparation via thiol- or amino-containing antibody fragment intermediates
A process for preparing a compound of formula (I) by reacting thiol- or amino-containing antibody or antigen binding fragments with formula (II) derivatives to form intermediates of formulas IA, IC, and TB, followed by possible interconversion among formula (I) species or protected derivatives.
Specific binding moiety as CD20 antibody or fragment thereof
The compound according to claim 1, wherein the antibody or antigen binding fragment is selected from a CD20 antibody or a fragment thereof.
EGFR antibody or fragment with sequence identity constraint
The compound according to claim 1, wherein the antibody or antigen binding fragment is an EGFR antibody or fragment thereof having at least 80% sequence identity to SEQ ID NOS: 1 to 4.
Coverage centers on the formula (I) immunoconjugate defined by antibody or antigen binding fragment attachment, spacer/linker motifs S1 and S2, a carbohydrate molecule F capable of binding to a human anti-alpha-galactosyl antibody, and an aryl core Cy. The claims also include a preparation process using thiol- or amino-containing antibody or antigen binding fragments and dependent narrowing to CD20 and EGFR binding moieties.
Stated Advantages
Enhances immune recruitment while retaining target binding.
Alpha-Gal unit loading and linker-to-antibody ratio are characterized for the conjugates.
Documented Applications
Treating a bacterial infection by administering to a person in need a compound of claim 1 or a pharmaceutically acceptable salt thereof.
Targeting EGFR/cetuximab, HER2, CD20/rituximab, and pathogen targets including S. aureus and P. aeruginosa.
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