MODULAR PROTEIN DRUG CONJUGATE THERAPEUTIC
The invention provides modular antibody-therapeutic agent conjugates and antibody-detectable-agent conjugates, and methods of using said conjugates in therapeutic and diagnostic procedures.
1 . A conjugate comprising:
(a) a polypeptide active agent conjugation module to which one or more active agents are covalently bound, the one or more active agents selected from therapeutic agents and diagnostic agents; and
(b) a polypeptide targeting module comprising two Fc polypeptides and one or more antigen-binding domains, said targeting module covalently bound to said active agent conjugation module.
2 . The conjugate according to claim 1 , wherein said one or more active agents are therapeutic agents.
3 . The conjugate according to claim 2 , wherein said one or more therapeutic agents are selected from Maytansinoids, Auristatins, Dolastatins, Calicheaminicin, Vinca Alkaloids, kinase inhibitors, alkylating agents and purine analogs.
4 . (canceled)
5 . The conjugate according to claim 1 , wherein said targeting module is free from covalently bound active agent.
6 . (canceled)
7 . (canceled)
8 . (canceled)
9 . The conjugate according to claim 1 , wherein said active agent is bound to a cysteine, lysine, or an analog or modified version thereof.
10 . The conjugate according to claim 1 , wherein said active agent conjugation module comprises albumin or an albumin fragment.
11 . The conjugate according to claim 10 , wherein said albumin fragment comprises amino acids 381 to 585 of wild type Albumin.
12 . (canceled)
13 . The conjugate according to claim 1 , wherein a linker is interposed in said conjugate between said active agent and said active agent conjugation module; between said active agent conjugation module and said targeting module, or a combination thereof.
14 . (canceled)
15 . The conjugate according to claim 1 , wherein said targeting module is a one-armed antibody.
16 . The conjugate according to claim 15 , wherein said one-armed antibody comprises a heterodimeric Fc domain fused to a single Fab arm.
17 . (canceled)
18 . A method of treating a disease in a subject in need of such treatment, said method comprising: administering to said subject therapeutically effective amount of a conjugate according to claim 2 .
19 . (canceled)
20 . (canceled)
21 . A conjugate comprising:
(a) a polypeptide therapeutic agent conjugation module to which one or more therapeutic agents are covalently bound, said therapeutic agent conjugation module comprising albumin or an albumin fragment; and
(b) a polypeptide targeting module comprising two Fc polypeptides and one or more antigen-binding domains, said targeting module covalently bound to said therapeutic agent conjugation module, wherein at least one of said antigen-binding domains specifically binds to HER2/neu.
22 . The conjugate according to claim 21 , wherein said targeting module is a one-armed antibody comprising antigen-binding domain sequences of trastuzumab.
23 . The conjugate according to claim 21 , wherein said two Fc polypeptides form a heterodimeric Fc domain.
24 . The conjugate according to claim 21 , wherein said one or more therapeutic agents comprise a maytansoid, and said therapeutic agent conjugation module is an albumin fragment.
25 . The conjugate according to claim 21 , wherein said therapeutic agent conjugation module is covalently bound to the C-terminus or the N-terminus of said targeting module.
26 . (canceled)
27 . The conjugate according to claim 21 , wherein a linker is interposed in said conjugate between said therapeutic agent and said therapeutic agent conjugation module; between said therapeutic agent conjugation module and said targeting module, or a combination thereof.
28 . The conjugate according to claim 21 , wherein said conjugate comprises:
Heavy Chain A (SEQ. ID. NO.: 12), Heavy Chain B (SEQ. ID. NO.: 14), and light chain (SEQ. ID. NO.: 16).
29 . (canceled)
30 . (canceled)
31 . The conjugate according to claim 1 , wherein said active agent conjugation module is covalently bound to the C-terminus or the N-terminus of said targeting module.
32 . The conjugate according to claim 1 , wherein said active agent conjugation module comprises a lysine rich polypeptide.
33 . The conjugate according to claim 1 , wherein said active agent conjugation module comprises a fragment of albumin, a ubiquitin or a cell penetrating peptide.
34 . The conjugate according to claim 1 , wherein said targeting module comprises two Fc polypeptides and one antigen-binding domain.
35 . The conjugate according to claim 34 , wherein said antigen-binding domain is a Fab fragment or scFv.
36 . The conjugate according to claim 1 , wherein said two Fc polypeptides form a heterodimeric Fc domain.
37 . The conjugate according to claim 36 , wherein said heterodimeric Fc domain comprises one or more amino acid modifications in at least one CH3 sequence compared to a wild-type CH3 sequence.
38 . The conjugate according to claim 37 , wherein the heterodimeric Fc domain comprises the amino acid modifications:
(a) A:L231Y_F405A_Y407V, B:T366L_K392M_T394W;
(b) A:L231Y_F405A_Y407V, B:T366L_K392L_T394W;
(c) A:T350V_L351Y_F405A_Y407V, B:T350V_T366L_K392L_T394W;
(d) A:T350V_L351Y_F405A_Y407V, B:T350V_T366L_K392M_T394W, or
(e) A:T350V_L351Y_S400E_F405A_Y407V, B:T350V_T366L_N390R_K392M_T394W,
wherein the amino acid numbering is EU-numbering.
39 . The conjugate according to claim 1 , wherein the targeting module binds to a tumor-associated antigen.
40 . The conjugate according to claim 39 , wherein the tumor-associated antigen is an ErbB receptor associated antigen.
41 . The conjugate according to claim 21 , wherein said targeting module comprises two Fc polypeptides and one antigen-binding domain.
42 . The conjugate according to claim 41 , wherein said antigen-binding domain is a Fab fragment or scFv.
43 . The conjugate according to claim 23 , wherein said heterodimeric Fc domain comprises one or more amino acid modifications in at least one CH3 sequence compared to a wild-type CH3 sequence.
44 . The conjugate according to claim 43 , wherein the heterodimeric Fc domain comprises the amino acid modifications:
(a) A:L351Y_F405A_Y407V, B:T366L_K392M_T394W;
(b) A:L531Y_F405A_Y407V, B:T366L_K392L_T394W;
(c) A:T350V_L351Y_F405A_Y407V, B:T350V_T366L_K392L_T394W;
(d) A:T350V_L351Y_F405A_Y407V, B:T350V_T366L_K392M_T394W, or
(e) A:T350V_L351Y_S400E_F405A_Y407V, B:T350V_T366L_N390R_K392M_T394W,
wherein the amino acid numbering is EU-numbering.
45 . A method of treating cancer in a subject in need of such treatment, said method comprising: administering to said subject a therapeutically effective amount of a conjugate according to claim 21 .