Process for the synthesis of linker-drug vc-seco-DUBA
Inventors
JANOUSEK, Vladimir • Kas, Martin
Assignees
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Publication Number
US-11633492-B2
Publication Date
2023-04-25
Expiration Date
Abstract
The compound of formula (II) is an advantageous intermediate for improving the process of synthesizing the linker-drug vc-seco-DUBA, as well as for the overall process for preparing an antibody-drug conjugate comprising the vc-seco-DUBA linker-drug. The methods of making the compound of formula (II) can include recovery of the compound as a solid, such as via crystallization, in high yields and purity.
Core Innovation
The invention relates to improved industrial-scale synthesis of vc-seco-DUBA of formula (I). It prepares and isolates a compound of formula (II) as a key intermediate, uses hydrogen chloride in 1,4-dioxane to form compound (II), and uses crystallization of the intermediate to improve purity and yield in the overall synthesis.
The disclosure describes reacting a compound of formula (II) with a compound of formula (VII) to form vc-seco-DUBA of formula (I), and includes a conjugation-type reaction step involving maleimide-OEG2-val-cit-PABA-PNP (6). It also describes removal of MOM and Boc protecting groups using hydrogen chloride in 1,4-dioxane with a scavenger system, followed by crystallization to provide the intermediate with high purity.
The document further relates to subsequent conjugation of vc-seco-DUBA to form antibody-drug conjugates (ADCs), including trastuzumab-based constructs, with drug-to-antibody ratio ranges of 1 to 8, optionally 1 to 4 or 2.6 to 2.9. It indicates that the overall synthesis is a sequence of coupled intermediates leading to vc-seco-DUBA.
Claims Coverage
The claims coverage is grounded in five inventive features across the independent claims: a crystalline solid compound of formula (II), formation of compound (II) from compound (III) using hydrogen chloride in 1,4-dioxane, synthesis of vc-seco-DUBA (formula I) from compound (II) and compound (VII), and conjugation of vc-seco-DUBA to an antibody or antigen-binding fragment to form an antibody-drug conjugate with an average drug-to-antibody ratio from 1 to 8.
Crystalline solid compound of formula (II)
A compound of formula (II), in solid form, limited further to a crystalline solid form.
Hydrogen chloride in 1,4-dioxane formation of compound (II)
Reacting a compound of formula (III) with hydrogen chloride in 1,4-dioxane to form the compound of formula (II).
Synthesis of vc-seco-DUBA from compound (II) and compound (VII)
Reacting a compound of formula (II) with a compound of formula (VII) to form vc-seco-DUBA of formula (I).
Antibody-drug conjugate synthesis with defined drug-to-antibody ratio
Conjugating vc-seco-DUBA of formula (I) to an antibody or an antigen-binding fragment thereof to form an antibody-drug conjugate of formula (VIII) with an average drug-to-antibody ratio m from 1 to 8.
Across the independent claims, the coverage focuses on the solid-state definition of intermediate compound (II), the hydrogen chloride in 1,4-dioxane conversion of formula (III) to formula (II), formation of vc-seco-DUBA (I) from compound (II) and compound (VII), and conjugation of vc-seco-DUBA to obtain antibody-drug conjugates (VIII) with m from 1 to 8.
Stated Advantages
Crystallization of intermediate II unexpectedly increases purity from 94 to 96% to at least 99.0%.
Crystallization of intermediate II improves vc-seco-DUBA yield from 53% to about 79%.
Compared with the prior four-step route of WO2011/133039, the disclosed approach addresses low yields.
Improves overall vc-seco-DUBA yield versus prior art conditions.
Provides vc-seco-DUBA with reported UPLC-IN and purity metrics of at least 90% UPLC-IN and at least 99% purity, and reported isolated yield.
Documented Applications
Production of trastuzumab-based antibody-drug conjugates (ADCs) using vc-seco-DUBA, with disclosed DAR ranges of 1 to 8, optionally 1 to 4 or 2.6 to 2.9.
Synthesis of an antibody-drug conjugate of formula (VIII) by conjugating vc-seco-DUBA of formula (I) to an antibody or an antigen-binding fragment thereof.
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