Toxin conjugates

• US 6,103,236 A
• Filed: 11/10/1997
• Issued: 08/15/2000
• Est. Priority Date: 05/10/1995
• Status: Expired due to Fees

• Current Assignee: Kyowa Hakko Kirin Company Limited (Kirin Holdings Company Limited)
• Original Assignee: Kyowa Hakko Kogyo Company Limited (Kirin Holdings Company Limited)
• Inventors: Ohta, So, Yamasaki, Motoo, Hanai, Nobuo, Saito, Hiromitsu, Suzawa, Toshiyuki, Nagamura, Satoru
• Primary Examiner(s): MacMillan, Keith D.
• Assistant Examiner(s): Ponnahuri, P.
• Application Number:
  US08/981,416
• Time in Patent Office: 1,009 Days
• Field of Search: 435/331, 530/391.7, 530/391.9, 530/391.1, 530/866, 530/867, 424/179.1, 424/193.1, 424/183.1, 424/236.1, 424/178.1, 424/237.1
• US Class Current: 424/183.1
• CPC Class Codes: A61K 39/44 Antibodies bound to carriers
• CPC Class Codes: A61K 47/6809 Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
• CPC Class Codes: A61K 47/6817 Toxins
• CPC Class Codes: A61K 47/6889 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 Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 17/06 attached to the carrier via a bridging agent

Abstract

The present invention relates to a toxin conjugate in which a residue derived from a compound having an affinity for a target cell is bound to a toxin through a spacer comprising polyalkylene glycol and dipeptide.

Claims

1. A toxin conjugate in which a compound having an affinity for a target cell is bound to a toxin through a spacer consisting essentially of polyalkylene glycol and a dipeptide.

9. A toxin conjugate according to claim 1, wherein said toxin conjugate has a structure selected from the group consisting of

NL-1-(PEG-Ala-Val-ADM)m

NL-1-(PEG-Ala-Pro-ADM)m

NL-1-(PEG-Gly-Pro-ADM)m

KM-231-(PEG-Ala-Val-DNR)m

KM-231-(PEG-Ala-Pro-DNR)m

KM-231-(PEG-Gly-Pro-DNR)m

NL-1-(PEG-Ala-Val-Compound (20))m

NL-1-(PEG-Ala-Pro-Compound (20))m

NL-1-(PEG-Gly-Pro-Compound (20))m

KM-231-(PEG-Ala-Val-Compound 12)m

KM-631-(PEG-Ala-Val-Compound 12)m,

wherein NL-1, MK-231 and KM-631 are monoclonal antibodies, and ADM is adriamycin and DNR is daunorubicin.

2. A toxin conjugate represented by formula (I)

View Dependent Claims (3, 4, 5, 6, 7, 8, 10)

3. The toxin conjugate according to claim 2, wherein the group capable of binding to X¹ is CO, N, S or O, and Y¹ has a group selected from N, S or O, provided that when X¹ is S, Z is bound to X¹ via CO of Z, and when X¹ is a group other than S, Z is bound to X¹ via N, S or O of Z, and Y¹ is bound to W or R² through N, S or O of Y¹.

4. The toxin conjugate according to claim 2 or 3, wherein Z is a protein or a peptide.

5. The toxin conjugate according to claim 4, wherein the protein is an antibody or an antibody fragment.

6. The toxin conjugate according to claim 2 wherein R¹ represents an alanine residue, a leucine residue, or a glycine residue;

and R² represents a proline residue, a valine residue, or a leucine residue.

7. The toxin conjugate according to claim 2 wherein Y¹ is adriamycin, daunorubicin, a duocarmycin derivative, mitomycin A, mitomycin C, ricin A, diphtheria toxin, or Pseudomonas exotoxin.

8. A toxin conjugate according to claim 2, wherein said compound having an affinity for a target cell has a group capable of binding to X¹ selected from the group consisting of COOH, NH, SH and OH.

10. A toxin conjugate according to claim 3, wherein said Y¹ is bound to R² through N, S or O, when W represents a single bond.

11. A toxin conjugate in which a compound having an affinity for a target cell is bound to a toxin through a spacer consisting of a polyalkylene glycol and a dipeptide.