US 2022/0017462 A1Published application

Ortho-phthalaldehyde containing linkers and use for preparation of antibody-drug conjugate

OwnerXuechen LI, Mingzhi JIN +3inventors

InventorsXuechen LI, Mingzhi JIN, Yue ZHANG, Li YIN, Jun WANG

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Abstract

Provided herein are novel ortho-Phthalaldehyde (OPA) containing linkers (OPA-L) and the use of OPA-L for the preparation of Antibody-drug conjugate (ADC) via the formation of Phthalimidine through the reaction of primary amine on antibody (e.g., residue of Lysine) and ortho-Phthalaldehyde. The advantage of this OPA-L is high reactivity and can be applied in different types of antibodies to form stably-linked conjugates. The use of OPA-L for the preparation of ADC is advantageous for mild and wide condition of conjugation, for instance, low percentage of organic solvent required, wide range of pH and temperature can be used.

Claims20

Dependent claims

A compound of the following formula (I):

OPA-L (I)
Wherein
OPA is
L includes
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, heteroaryl, alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, heterocycloalkylene;
—(CH2)m-, wherein one or more CH2 are replaced by one or more groups selected from NH and C═O, m is an integer of 0-20;
—(CH2)n-heteroaryl, wherein one or more CH2 are replaced by one or more groups selected from —NH, —C═O and —O—, n is an integer of 0-20;
—(CH2)o-heterocycloalkyl-(CH2)o-CH3, wherein one or more CH2 are replaced by one or more groups selected from NH and C═O, o is an integer of 0-20;
—(CH2)q-cycloalkyl-(CH2)q-CH3, wherein one or more CH2 are replaced by one or more groups selected from NH and C═O, p is an integer of 0-20;
—(CH2)r-cycloalkyl-(CH2)r-heteroaryl, wherein one or more CH2 are replaced by one or more groups selected from NH and C═O, r is an integer of 0-20;
peptide like di-peptides, tri-peptides, tetra-peptide, penta-peptide;
oligosaccharide, polyethylene glycol (PEG), and the combinations thereof, and
said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkynyl, aryl, heteroaryl, —CH3, heterocycloalkenyl, alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, heterocycloalkylene are optionally substituted by at least one substituents.

10 more elements

A compound of the following formula (II):

OPA-L-D (II)
Wherein
OPA is
L includes alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl,
heterocycloalkenyl, heterocycloalkynyl, aryl, heteroaryl, alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, heterocycloalkylene;
—(CH2)m-, wherein one or more CH2 are replaced by one or more groups selected from NH and C═O, m is an integer of 0-20;
—(CH2)n-heteroaryl, wherein one or more CH2 are replaced by one or more groups selected from NH, C═O and —O—, n is an integer of 0-20;
—(CH2)o-heterocycloalkyl-(CH2)o-CH3, wherein one or more CH2 are replaced by one or more groups selected from NH and C═O, o is an integer of 0-20;
—(CH2)q-cycloalkyl-(CH2)q-CH3, wherein one or more CH2 are replaced by one or more groups selected from NH and C═O, p is an integer of 0-20;
—(CH2)r-cycloalkyl-(CH2)r-heteroaryl, wherein one or more CH2 are replaced by one or more groups selected from NH and C═O, r is an integer of 0-20;
peptide;
oligosaccharide, polyethylene glycol (PEG), and the combinations thereof, and said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkynyl, aryl, heteroaryl, —CH3, heterocycloalkenyl, alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, heterocycloalkylene are optionally substituted by at least one substituents;
D is independently active reagent, wherein said active reagent includes an anti-cancer reagent such as Mertansine and MMAE;
an anti-inflammation reagent;
Fluorescein such as FTIC;
a peptide;
a protein;
a nucleotide;
an oligonucleotide;
a chemotherapy drug;
a natural product;
an immune modulator;
a tubulin-binder;
a DNA-alkylating agent;
an HSP90 inhibitor;
a DNA topoisomerase inhibitor;
an anti-epigenetic agent;
an HDAC inhibitor;
an anti-metabolism agent;
a proteasome inhibitor;
a peptidomimetic;
an siRNA;
an antisense DNA;
epothilone A, epothilone B, or paclitaxel.

31 more elements

A compound of the following formula (III):

Ab-(OPA-L-D)p (III)
wherein
Ab is a cell binding reagent, wherein said cell binding reagent includes IgGs, bi-specific antibody, antibody fragment such as Fab, Fab′, F(ab′)2 and scFv, Heavy-chain only antibody or Nanobody;
OPA is
L includes alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, heteroaryl, alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, heterocycloalkylene;
—(CH2)m-, wherein one or more CH2 are replaced by one or more groups selected from NH and C═O, m is an integer of 0-20;
—(CH2)n-heteroaryl, wherein one or more CH2 are replaced by one or more groups selected from NH, C═O and —O—, n is an integer of 0-20;
—(CH2)o-heterocycloalkyl-(CH2)o-CH3, wherein one or more CH2 are replaced by one or more groups selected from NH and C═O, o is an integer of 0-20;
—(CH2)q-cycloalkyl-(CH2)q-CH3, wherein one or more CH2 are replaced by one or more groups selected from NH and C═O, p is an integer of 0-20;
—(CH2)r-cycloalkyl-(CH2)r-heteroaryl, wherein one or more CH2 are replaced by one or more groups selected from NH and C═O, r is an integer of 0-20;
peptide;
oligosaccharide, polyethylene glycol (PEG), and the combinations thereof, and said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkynyl, aryl, heteroaryl, —CH3, heterocycloalkenyl, alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, heterocycloalkylene are optionally substituted by at least one substituents;
D is independently active reagent, wherein said active reagent includes an anti-cancer reagent such as Mertansine and MMAE;
an anti-inflammation reagent;
Fluorescein such as FTIC;
a peptide;
a protein;
a nucleotide;
an oligonucleotide;
a chemotherapy drug;
a natural product;
an immune modulator;
a tubulin-binder;
a DNA-alkylating agent;
an HSP90 inhibitor;
a DNA topoisomerase inhibitor;
an anti-epigenetic agent;
an HDAC inhibitor;
an anti-metabolism agent;
a proteasome inhibitor;
a peptidomimetic;
an siRNA;
an antisense DNA;
epothilone A, epothilone B, or paclitaxel;
p is a integer refers to the number of active reagent attached to cell binding reagent, wherein p is an integer of 0-15.

32 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/296,088Filed 21 Nov 2019
Priority: CN PCT/CN2018/11725723 Nov 2018
Published: 20 Jan 2022
Term ends: Not estimatedThe source records don’t support an estimate.

Classification19 codes

A61K 47/6889
The modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment: conjugates wherein the antibody being the…
A61K 47/68033
Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates: the drug being a maytansine
A61K 47/6855
The antibody targeting a determinant of a tumour cell: the tumour determinant being from breast cancer cell
C07C 233/61
Having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings: having the nitrogen atom of at…

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