JPWO2022246086A5 - - Google Patents

Description

While several embodiments have been described, it will be apparent that the inventors' basic examples may be modified to provide other embodiments that utilize the techniques (e.g., compounds, agents, compositions, methods, etc.) of the present disclosure.
The present application also includes the following aspects.
[Aspect 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 -LLG ^,
RLG 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 amino acid analog;
t is 0 to 50;
z is 1 to 50;
each R ^c is independently -L ^a -R';
each L ^a is independently a covalent bond or an optionally substituted divalent group selected from C ₁ -C ₂₀ aliphatic or C ₁ -C ₂₀ heteroaliphatic having 1 to 5 heteroatoms, wherein one or more methylene units of said 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 divalent monocyclic, bicyclic, or polycyclic group, and each monocyclic ring is independently selected from a C 3-20 alicyclic _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 ^RG4 -L ^RG1 -L ^RG2 -, -L ^LG2 -L ^LG3 -L ^LG4 -L ^RG1 -L ^RG2 -,
Each of LLG1 , LLG2 ^, LLG3 ^, LLG4 ^, LRG1 ^, LRG2 ^{, and} LRM ^is independently L;
each L is independently a covalent bond or a divalent optionally substituted linear or branched C 1-100 group comprising one or more aliphatic moieties, aryl moieties, heteroaliphatic moieties each independently having 1 to 20 heteroatoms, heteroaromatic moieties each independently having 1 to 20 heteroatoms, or any combination of any one or more of such moieties, wherein one or more methylene units of said group are optionally and independently selected from C _1-6 alkylene, C _1-6 alkenylene, a divalent C 1-6 heteroaliphatic group having 1 to ₅ heteroatoms _,
, -Cy-, -C(R') ₂ -, -O-, -S-, -SS-, -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 is replaced by 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 to 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 C1-30 _aliphatic , C1-30 heteroaliphatic having 1-10 heteroatoms , C6-30 aryl, C6-30 arylaliphatic, _C6-30 arylheteroaliphatic _having 1-10 heteroatoms, _5-30 membered heteroaryl having 1-10 heteroatoms, and _3-30 membered heterocyclyl having 1-10 heteroatoms;
the two R groups, optionally and independently, together form a covalent bond; or
two or more R groups on the same atom optionally and independently combine with said atom to form an optionally substituted 3-30 membered monocyclic, bicyclic, or polycyclic ring having, in addition to said atom, 0-10 heteroatoms; or
two or more R groups on two or more atoms optionally and independently, taken together with their intervening atoms, form an optionally substituted 3-30 membered monocyclic, bicyclic, or polycyclic ring having, in addition to said intervening atoms, 0-10 heteroatoms;
MOI is a moiety of interest that includes monomethyl auristatin E (MMAE), a compound or a salt thereof.
[Aspect 2]
2. The compound or salt of aspect 1, wherein LG is or comprises a target binding moiety that binds to a targeting agent, said targeting agent being an antibody agent.
[Aspect 3]
3. The compound or salt of aspect 1 or 2, wherein LG is or comprises a target binding moiety that binds to the Fc region of an antibody drug.
[Aspect 4]
A compound or salt according to any one of the preceding aspects, wherein LG is or comprises a target binding moiety that binds to a targeted agent, and said targeted agent is an antibody drug that is or comprises enfortumab, brentuximab, or trastuzumab.
[Aspect 5]
The compound or salt of any one of the preceding aspects, wherein LG is or includes a group selected from any of A-1 to A-50 of Table A-1.
[Aspect 6]
^A compound or salt according to any one of the preceding aspects, wherein RLG 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.
[Aspect 7]
The compound is
The compound or salt according to any one of the preceding aspects, comprising one or more groups selected from:
[Aspect 8]
The compound or salt according to any one of the preceding aspects ^, wherein LRM is or comprises -( _CH2CH2O )n-, where n is independently selected at each occurrence from the integers 2, 3, 4, 5, 6, 7, and 8 _.
[Aspect 9]
^A compound or _salt according to any one of the preceding aspects, wherein LRM 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 the integers 1, 2, 3, and 4.
[Aspect 10]
A drug having the structure of P-I,
P-L ^PM -MOI
(P-I)
or a salt thereof, comprising the steps of:
P is a targeting drug moiety;
L ^PM is a linker,
MOI is a moiety of interest that is or comprises monomethyl auristatin E (MMAE);
1) a targeting agent and 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 that comprises a target binding moiety that binds to a targeting agent;
RG is a reactive group,
L ^RM is a linker;
The MOI is MMAE or a moiety of interest comprising same;
2) forming an agent having a structure of formula P-I; or
Drugs with the structure of P-II
P-N-L ^PM -MOI
(P-II)
A process for preparing a compound of formula
P-N is a protein drug moiety containing a lysine residue;
L ^PM is a linker,
MOI is a moiety of interest that is or comprises monomethyl auristatin E (MMAE);
The method further comprising:
P-N and 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 that contains a protein binding moiety that is attached to P-N;
RG is a reactive group,
L ^RM is a linker;
The MOI is MMAE or a moiety of interest comprising same.
[Aspect 11]
11. The method of aspect 10, wherein the targeting agent is or comprises an antibody agent.
[Aspect 12]
The method of aspect 10, wherein said antibody drug is or comprises an anti-CD30 monoclonal antibody, such as brentuximab, or an anti-nectin-4 monoclonal antibody, such as enfortumab.
[Aspect 13]
13. The method of claim 11 or 12, wherein said moiety of interest is selectively attached to said antibody drug at K246 or K248 of the IgG1 heavy chain, or a corresponding position.
[Aspect 14]
13. The method of claim 11 or 12, wherein said moiety of interest is selectively attached to said antibody drug at K251 or K253 of the IgG2 heavy chain, or a corresponding position.
[Aspect 15]
13. The method of claim 11 or 12, wherein said moiety of interest is selectively attached to said antibody drug at K239 or K241 of the IgG4 heavy chain, or a corresponding position.
[Aspect 16]
13. The method of any one of aspects 10 to 12, wherein the contacting and forming steps are performed in one chemical reaction.
[Aspect 17]
A composition providing multiple agents, each of which independently comprises:
an antibody drug moiety;
a moiety of interest that is or comprises monomethyl auristatin E (MMAE);
optionally, a linker moiety connecting the antibody drug portion and the moiety of interest;
the antibody drug moieties of the multiple agents comprise a common amino acid sequence or are capable of binding to a common antigen, and the multiple agents independently share a common modification at at least one common amino acid residue of the antibody drug moieties;
A composition, wherein about 1% to 100% of all drugs comprising an antibody drug portion that comprises said common amino acid sequence or is capable of binding to said common antigen and said moiety of interest are in said plurality of drugs.
[Aspect 18]
20. The composition of aspect 17, wherein the antibody drug portions of said multiple agents are capable of binding to a common antigen.
[Aspect 19]
Aspect 19. The composition of aspect 18, wherein the common amino acid residue is K246 or K248 of an IgG1 antibody heavy chain, or an amino acid residue corresponding thereto.
[Aspect 20]
Aspect 19. The composition of aspect 18, wherein the common amino acid residue is K251 or K253 of an IgG2 antibody heavy chain, or an amino acid residue corresponding thereto.
[Aspect 21]
Aspect 19. The composition of aspect 18, wherein the common amino acid residue is K239 or K241 of an IgG4 antibody heavy chain, or an amino acid residue corresponding thereto.
[Aspect 22]
19. The composition of aspect 18, wherein each of said plurality of agents does not contain -S-Cy-, where -Cy- is an optionally substituted 5-membered monocyclic ring, does not contain -S-S- that is not formed by a cysteine residue, and does not contain -SH or a salt form thereof that is not of a cysteine residue.
[Aspect 23]
20. The composition of aspect 18, wherein each of said multiple agents does not contain --S--CH ₂ --CH ₂ --.
[Aspect 24]
below
20. The composition of claim 18, comprising one or more groups selected from:
[Aspect 25]
RLG is ^​
Polypeptides
or the following compound:
or a salt thereof. 2. The compound according to aspect 1, wherein R ^c -(Xaa)z- comprises at least one amino acid residue selected from the group consisting of:
[Aspect 26]
The compound is
2. The compound or salt according to embodiment 1, selected from:
[Aspect 27]
A compound having the structure of formula R-I,
LG-RG-L ^RM -MOI
(R-I)
or a salt thereof, wherein
LG is a group that comprises a target binding moiety that binds to a targeting agent;
RG is a reactive group,
L ^RM is a linker;
MOI is the moiety of interest including MMAE,
the targeting agent is an antibody comprising an IgG heavy chain comprising K246 or K248;
The target binding moiety is configured to bind to the antibody in such a way as to bring the reactive group into proximity with K246 or K248 of the IgG heavy chain, allowing a reaction between K246 or K248 and the reactive group, resulting in attachment of a moiety comprising an L RM -MOI to K246 or K248 ^, and removal of the group containing the target binding moiety from the compound, or a salt thereof.
[Aspect 28]
A compound having the structure of formula R-I,
LG-RG-L ^RM -MOI
(R-I)
or a salt thereof, wherein
LG is a group that comprises a target binding moiety that binds to a targeting agent;
RG is a reactive group,
L ^RM is a linker;
MOI is a moiety of interest that includes monomethyl auristatin E (MMAE), a compound or a salt thereof.
[Aspect 29]
1. A composition comprising:
Structure of Formula (P-II)
P-N-L ^PM -MOI (P-II)
A first compound having the formula:
P-N is a protein drug moiety containing a lysine residue;
L ^PM is a linker,
The MOI comprises a first compound, which is a moiety of interest comprising monomethyl auristatin E (MMAE);
The following structure:
LG-OH (LG-I)
wherein LG is a group that comprises a target binding moiety that binds to a targeting agent.
[Aspect 30]
Formula (RI)
LG-RG-L ^RM -MOI (R-I)
A third compound having the formula:
LG is a group containing a target binding moiety that binds to a targeting agent, and is the same as LG in formula (LG-I);
RG is a reactive group,
L ^RM is a linker and is the same as in formula (P-II);
the MOI is a third compound, which is a moiety of interest comprising monomethyl auristatin E (MMAE);
Formula (R-III)
HO-RG-L ^RM -MOI (R-III)
or a combination thereof.

Claims (30)

Formula RI :
LG-RG-L ^RM -MOI
(R-I)
[During the ceremony,
LG is R ^{LG -LLG} ,
^RLG 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 amino acid analog;
t is 0 to 50;
z is 1 to 50;
each R ^c is independently -L ^a -R';
each L ^a is independently a covalent bond or an optionally substituted divalent group selected from C ₁ -C ₂₀ aliphatic or C ₁ -C ₂₀ heteroaliphatic having 1 to 5 heteroatoms, wherein one or more methylene units of said group are optionally 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 divalent monocyclic, bicyclic, or polycyclic group, and each monocyclic ring is independently selected from a C _3-20 alicyclic 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 ^RG4 -L ^RG1 -L ^RG2 -, -L ^LG2 -L ^LG3 -L ^LG4 -L ^RG1 -L ^RG2 -,
Each of ^LLG1 , ^LLG2 , ^LLG3 , ^LLG4 , ^LRG1 , ^LRG2 , and ^LRM is independently L;
each L is independently a covalent bond or a divalent, optionally substituted, linear or branched C 1-100 group comprising one or more aliphatic moieties, aryl moieties, heteroaliphatic moieties each independently having 1 to 20 heteroatoms, heteroaromatic moieties each independently having _{1 to 20 heteroatoms} , or any combination of any one or more of such moieties, wherein one _{or more} methylene units of said group are independently selected from the group ...
-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 may be replaced by 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 to 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 _C1-30 aliphatic, C1-30 heteroaliphatic having 1-10 heteroatoms, _C6-30 aryl, _C6-30 arylaliphatic, _C6-30 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 may independently be joined together to form a covalent bond; or two or more R groups on the same atom may independently be joined together to form an optionally substituted 3-30 membered monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms in addition to said atom; or two or more R groups on two or more atoms may independently , together with their intervening atoms, form an optionally substituted 3-30 membered monocyclic, bicyclic, or polycyclic ring having , in addition to said intervening atoms, 0-10 heteroatoms;
MOI is the moiety of interest containing monomethyl auristatin E (MMAE) .
A compound having the structure: or a salt thereof. 2. The compound or salt thereof of claim 1, wherein LG is or comprises a target binding moiety that binds to a targeting agent, and the targeting agent is an antibody agent. 3. The compound or salt thereof of claim 1 or 2, wherein LG is or comprises a target binding moiety that binds to the Fc region of an antibody drug. 4. The compound or salt thereof according to claim 3 , wherein LG is or comprises a target binding moiety that binds to a targeting agent, and the targeting agent is or comprises an antibody drug, enfortumab, brentuximab, or trastuzumab . LG is A-1 to A-50 in Table A-1 :
The compound according to claim 2 , or a salt thereof , which is or contains a group selected from the following: 2. The compound or salt thereof according to claim 1 , wherein ^RLG is or comprises DCAWXLGELVWCT (SEQ ID NO: 18), wherein the two cysteine residues may form a disulfide bond, and X is an amino acid residue. The compound or a salt thereof is
2. The compound or salt thereof according to claim 1 , comprising one or more groups selected from: 2. The compound of claim 1 , wherein ^LRM is or comprises -(CH ₂ CH ₂ O)n-, where n is independently selected at each occurrence from the integers 2, 3, 4, 5, 6, 7, and 8, or a salt thereof . 2. The compound of claim 1, or a salt thereof, wherein ^LRM 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 the integers 1 , 2, 3, and 4. P-I :
P-L ^PM -MOI
(P-I)
[During the ceremony,
P is a targeting drug moiety;
L ^PM is a linker,
MOI is monomethyl auristatin E (MMAE) or a moiety of interest that contains same .
or a salt thereof, comprising the steps of:
1) A targeting agent and a compound of formula R-I :
LG-RG-L ^RM -MOI
(R-I)
[During the ceremony,
LG is a group that comprises a target binding moiety that binds to a targeting agent;
RG is a reactive group,
L ^RM is a linker;
The MOI is MMAE or a moiety of interest that contains it .
or a salt thereof ;
2) forming a compound having a structure of formula P-I or a salt thereof ;
A method comprising:
Or P-II :
P-N-L ^PM -MOI
(P-II)
[During the ceremony,
P-N is a protein drug moiety containing a lysine residue;
L ^PM is a linker,
MOI is monomethyl auristatin E (MMAE) or a moiety of interest that contains same .
or a salt thereof, comprising the steps of:
P-N and a compound of the formula R-I :
LG-RG-L ^RM -MOI
(R-I)
[During the ceremony,
LG is a group that contains a protein binding moiety that is attached to P-N;
RG is a reactive group,
L ^RM is a linker;
The MOI is MMAE or a moiety of interest that contains it .
or a salt thereof with a reaction partner having the structure : The method of claim 10, wherein the targeting agent is or includes an antibody agent. The method of claim 10, wherein the antibody drug is or comprises an anti-CD30 monoclonal antibody, such as brentuximab, or an anti-nectin-4 monoclonal antibody, such as enfortumab. The method of claim 11 or 12, wherein the moiety of interest is selectively attached to the antibody drug at K246 or K248 of the IgG1 heavy chain, or a corresponding position. The method of claim 11 or 12, wherein the moiety of interest is selectively attached to the antibody drug at K251 or K253 of the IgG2 heavy chain, or a corresponding position. The method of claim 11 or 12, wherein the moiety of interest is selectively attached to the antibody drug at K239 or K241 of the IgG4 heavy chain, or a corresponding position. The method of claim 10 , wherein the contacting and forming steps occur in one chemical reaction. A composition providing multiple agents, each of which independently comprises:
an antibody drug moiety;
a moiety of interest that is or comprises monomethyl auristatin E (MMAE) ; and
and optionally including a linker moiety connecting the antibody drug portion and the moiety of interest;
the antibody drug moieties of the multiple agents comprise a common amino acid sequence or are capable of binding to a common antigen, and the multiple agents independently share a common modification at at least one common amino acid residue of the antibody drug moieties;
About 1% to 100% of all drugs that contain an antibody drug portion that contains the common amino acid sequence or is capable of binding to the common antigen and the moiety of interest are in the plurality of drugs.
composition. The composition of claim 17, wherein the antibody drug portions of the multiple drugs are capable of binding to a common antigen. The composition according to claim 18, wherein the common amino acid residue is K246 or K248 of an IgG1 antibody heavy chain, or a corresponding amino acid residue thereto. The composition according to claim 18, wherein the common amino acid residue is K251 or K253 of an IgG2 antibody heavy chain, or a corresponding amino acid residue thereto. The composition of claim 18, wherein the common amino acid residue is K239 or K241 of an IgG4 antibody heavy chain, or a corresponding amino acid residue thereto. 20. The composition of claim 18, wherein each of said plurality of agents does not contain -S-Cy-, where -Cy- is an optionally substituted 5-membered monocyclic ring, does not contain -S-S- that is not formed by a cysteine residue, and does not contain -SH or a salt form thereof that is not of a cysteine residue. 20. The composition of claim 18, wherein each of said multiple agents does not contain --S--CH ₂ --CH ₂ --. below
20. The composition of claim 18, comprising one or more groups selected from: ^RLG is
Polypeptides ,
Or the following compound :
The compound or a salt thereof according to claim 1, wherein R ^c -(Xaa)z- includes at least one amino acid residue selected from the group consisting of: The compound or a salt thereof is
and
and their salts
The compound or salt thereof according to claim 1, selected from: Formula RI :
LG-RG-L ^RM -MOI
(R-I)
[During the ceremony,
LG is a group that comprises a target binding moiety that binds to a targeting agent;
RG is a reactive group,
L ^RM is a linker;
MOI is the moiety of interest containing MMAE.
or a salt thereof,
the targeting agent is an antibody comprising an IgG heavy chain comprising K246 or K248;
the target binding moiety is configured to bind to the antibody in such a way as to bring the reactive group into proximity with K246 or K248 of the IgG heavy chain, allowing a reaction between K246 or K248 and the reactive group, resulting in attachment of a moiety comprising an ^LRM -MOI to K246 or K248, and removal of the group containing the target binding moiety from the compound or salt thereof .
A compound or a salt thereof. Formula RI :
LG-RG-L ^RM -MOI
(R-I)
[During the ceremony,
LG is a group that comprises a target binding moiety that binds to a targeting agent;
RG is a reactive group,
L ^RM is a linker;
MOI is the moiety of interest containing monomethyl auristatin E (MMAE) .
A compound having the structure: or a salt thereof. 1. A composition comprising:
Formula (P-II) :
P-N-L ^PM -MOI (P-II)
[During the ceremony,
P-N is a protein drug moiety containing a lysine residue;
L ^PM is a linker,
MOI is the moiety of interest containing monomethyl auristatin E (MMAE) .
or a salt thereof ,
structure :
LG-OH (LG-I)
where LG is a group that contains a target binding moiety that binds to a targeting agent .
or a salt thereof ; and
A composition comprising: Formula (RI) :
LG-RG-L ^RM -MOI (R-I)
[During the ceremony,
LG is a group containing a target binding moiety that binds to a targeting agent, and is the same as LG in formula (LG-I);
RG is a reactive group,
L ^RM is a linker and is the same as L ^RM in formula (P-II);
MOI is the moiety of interest containing monomethyl auristatin E (MMAE) .
or a salt thereof ; or
Formula (R-III) :
HO-RG-L ^RM -MOI (R-III)
or a salt thereof;
or a combination thereof .