Antibody drug conjugates using mates technology for delivering cytotoxic agents

Patent metadata

Field	Value
Publication number	US-2025108124-A1
Application number	US-202218555858-A
Country	US
Kind code	A1
Filing date	May 19, 2022
Priority date	May 19, 2021
Publication date	Apr 3, 2025
Grant date	—

Abstract

Among other things, the present disclosure provides technologies for site-directed conjugation of various moieties of interest to target agents. In some embodiments, the present disclosure utilizes target binding moieties to provide high conjugation efficiency and selectivity. In some embodiments, provided technologies are useful for preparing antibody conjugates.

First claim

1 . A compound having the structure of formula R-I:
LG-RG-L RM -MOI  (R-I)
or a salt thereof, wherein:
LG is R LG -L LG ;
R LG is

 R c -(Xaa)z-, a nucleic acid moiety, or a small molecule moiety;
each Xaa is independently a residue of an amino acid or an amino acid analog;
t is 0-50;
z is 1-50;
each R c is independently -L a -R′;
each L a is independently a covalent bond, or an optionally substituted bivalent group selected from C 1 -C 20 aliphatic or C 1 -C 20 heteroaliphatic having 1-5 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced with —C(R′) 2 —, -Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O) 2 —, —S(O) 2 N(R′)—, —C(O)S—, or —C(O)O—;
each -Cy- is independently an optionally substituted bivalent monocyclic, bicyclic or polycyclic group wherein each monocyclic ring is independently selected from a C 3-20 cycloaliphatic ring, a C 6-20 aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms;
L LG is -L LG1 -, L LG1 -L LG2 , -L LG1 -L LG2 -L LG3 - or -L LG1 -L LG2 -L LG3 -L LG4 -;
RG is -L RG1 -L RG2 -, -L LG4 -L RG1 -L RG2 -, -L LG3 -L LG4 -L RG1 -L RG2 -, -L LG2 -L LG3 -L LG4 -L RG1 -L RG2 -;
each of L LG1 , L LG2 , L LG3 , L LG4 , L RG1 , L RG2 , and L RM is independently L;
each L is independently a covalent bond, or a bivalent optionally substituted, linear or branched C 1-100 group comprising one or more aliphatic moieties, aryl moieties, heteroaliphatic moieties each independently having 1-20 heteroatoms, heteroaromatic moieties each independently having 1-20 heteroatoms, or any combinations of any one or more of such moieties, wherein one or more methylene units of the group are optionally and independently replaced with C 1-6 alkylene, C 1-6 alkenylene, a bivalent C 1-6 heteroaliphatic group having 1-5 heteroatoms, —C≡C—, -Cy-, —C(R′) 2 —, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —C(O)C(R′) 2 N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O) 2 —, —S(O) 2 N(R′)—, —C(O)S—, —C(O)O—, —P(O)(OR′)—, —P(O)(SR′)—, —P(O)(R′)—, —P(O)(NR′)—, —P(S)(OR′)—, —P(S)(SR′)—, —P(S)(R′)—, —P(S)(NR′)—, —P(R′)—, —P(OR′)—, —P(SR′)—, —P(NR′)—, an amino acid residue, or —[(—O—C(R′) 2 —C(R′) 2 —) n ]—, wherein n is 1-20;
each R′ is independently —R, —C(O)R, —CO 2 R, or —SO 2 R;
each R is independently —H, or an optionally substituted group selected from C 1-30 aliphatic, C 1-30 heteroaliphatic having 1-10 heteroatoms, C 6-30 aryl, C 6-30 arylaliphatic, C 6-30 arylheteroaliphatic having 1-10 heteroatoms, 5-30 membered heteroaryl having 1-10 heteroatoms, and 3-30 membered heterocyclyl having 1-10 heteroatoms, or
two R groups are optionally and independently taken together to form a covalent bond, or:
two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms; or
two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms; and
MOI is a moiety of interest comprising monomethyl auristatin E (MMAE).

2 . The compound or salt of claim 1 , wherein LG is or comprises a target binding moiety that binds to a target agent, wherein the target agent is an antibody agent.

3 . The compound or salt of claim 1 or 2 , wherein LG is or comprises a target binding moiety that binds to the Fc region of an antibody agent.

4 . The compound or salt of any preceding claim wherein LG is or comprises a target binding moiety that binds to a target agent, wherein the target agent is an antibody agent that is or comprises enfortumab, brentuximab, or trastuzumab.

5 . The compound or salt of any preceding claim , wherein LG is or comprises a group selected from any of A-1 to A-50 in Table A-1.

6 . The compound or salt of any preceding claim , wherein R LG is or comprises DCAWXLGELVWCT (SEQ ID NO:18), wherein the two cysteine residues optionally form a disulfide bond, and X is an amino acid residue.

7 . The compound or salt of any preceding claim , wherein the compound comprises one or more groups selected from:

8 . The compound or salt of any preceding claim wherein L RM is or comprises —(CH 2 CH 2 O)n- where n is independently selected at each occurrence from integers 2, 3, 4, 5, 6, 7, and 8.

9 . The compound or salt of any preceding claim wherein L RM is or comprises —(CH 2 CH 2 O)n-(CH 2 )n-NHC(O)—(CH 2 )n-, —[(CH 2 CH 2 O)n-(CH 2 )n-NHC(O)]m-(CH 2 )n-, and —(CH 2 CH 2 O)n-(CH 2 )n-N((CH 2 CH 2 O)n-(CH 2 )n-)((CH 2 CH 2 O)n-(CH 2 )n-) where m is independently selected at each occurrence from integers 1, 2, 3, and 4.

10 . A method of preparing an agent having the structure of P-I:
P-L PM -MOI  (P—I)
or a salt thereof, wherein:
P is a target agent moiety;
L PM is a linker; and
MOI is a moiety of interest that is or comprises monomethyl auristatin E (MMAE) comprising steps of:
1) contacting the target agent with a reaction partner having the structure of formula R-I:
LG-RG-L RM -MOI  (R-I)

or a salt thereof, wherein:
LG is a group comprising a target binding moiety that binds to a target agent,
RG is a reactive group;
L RM is a linker; and
MOI is the moiety of interest that is or comprises MMAE; and
2) forming an agent having the structure of formula P—I; or
a method of preparing an agent having the structure of P-II:
P—N-L PM -MOI  (P-II)

wherein:
P—N is a protein agent moiety comprising a lysine residue;
L PM is a linker; and
MOI is a moiety of interest that is or comprises monomethyl auristatin E (MMAE);
the method comprising:
contacting P—N with a reaction partner having a structure of formula R-I:
LG-RG-L RM -MOI  (R-I)

or a salt thereof, wherein:
LG is a group comprising a protein-binding moiety that binds to P—N,
RG is a reactive group;
L RM is a linker; and
MOI is the moiety of interest that is or comprises MMAE.

11 . The method of claim 10 , wherein a target agent is or comprises an antibody agent.

12 . The method of claim 10 , wherein the antibody agent is or comprises an anti-CD30 monoclonal antibody, such as brentuximab or an anti-nectin-4-monoclonal antibody, such as enfortumab.

13 . The method of claim 11 or 12 , wherein the moiety of interest is selectively attached to the antibody agent at K246 or K248 of an IgG1 heavy chain or a corresponding location.

14 . The method of claim 11 or 12 , wherein the moiety of interest is selectively attached to the antibody agent at K251 or K253 of an IgG2 heavy chain or a corresponding location.

15 . The method of claim 11 or 12 , wherein the moiety of interest is selectively attached to the antibody agent at K239 or K241 of an IgG4 heavy chain or a corresponding location.

16 . The

Assignees

• Biohaven Therapeutics Ltd

Inventors

• Dubowchik Gene M
• Kazmierski Wieslaw
• Pracitto Richard
• Caldwell Reese M

Classifications

• A61K47/6855

  the tumour determinant being from breast cancer cell · CPC title

• A61K47/6861

  the tumour determinant being from kidney or bladder cancer cell · CPC title

• A61K47/6889 Primary

  Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment · CPC title

• A61K47/68031

  the drug being an auristatin · CPC title

• A61K47/65

  Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers · CPC title