Cytotoxic antibody conjugates and a process for preparation thereof

• US 5,030,719 A
• Filed: 04/27/1988
• Issued: 07/09/1991
• Est. Priority Date: 08/28/1986
• Status: Expired due to Fees

• Current Assignee: Teijin Limited
• Original Assignee: Teijin Limited
• Inventors: Hara, Takeshi, Umemoto, Naoji, Kato, Yoshinori
• Primary Examiner(s): Doll, John
• Assistant Examiner(s): Kim, Kay
• Application Number:
  US07/196,188
• Time in Patent Office: 1,168 Days
• Field of Search: 424/85.91, 530/391, 530/402, 530/389, 530/409, 530/410
• US Class Current: 530/391.9
• CPC Class Codes: A61K 47/6881 Cluster-antibody conjugates, i.e. the modifying agent consists of a plurality of antibodies covalently linked to each other or of different antigen-binding fragments covalently linked to each other
• CPC Class Codes: A61K 47/6895 Rescue therapy; Agonist-antagonist; Antidotes; Targeted rescue or protection, e.g. by folic acid-folinic acid or conjugated to antibodies
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

Cytotoxic antibody conjugates in which a folic acid-antagonistic folic acid analogue is bound to an antibody or its fragment through an oligopeptide. The conjugates can be used as a chemotherapeutic agent against malignant tumors.

Claims

1. Cytotoxic antibody conjugates wherein an antibody or its fragment which binds to antigenic cells is bound to a folic acid-antagonistic folic acid analgogue through an oligopeptide, wherein said cytotoxic antibody conjugate is represented by general formula (I)

(R'"'"'--CO--NH--Y--CO--NHNHCOCH.sub. 2 --NH) Ab (I)

where R'"'"' represents, together with CO, the residual group of a folic acid-antagonistic folic acid analogue, --NH--Y--CO--represents the residual group of an oligopeptide containing L-leucyl-L-alanyl-L-leucine, Ab represents an antibody or its fragment which bends to antigenic cells, and the N-atom adjacent to Ab is the nitrogen atom originating from the antibody or its fragment, and n is an integer of from 1 to 30.

2. Cytotoxic antibody conjugates according to claim 1 wherein the antibody is a monoclonal antibody.

3. Cytotoxic antibody conjugates according to claim 1 wherein the oligopeptide is L-leucyl-L-alanyl-L-leucyl-L-alanine, L-alanyl-L-leucyl-L-alanyl-L-leucine, or L-leucyl-L-alanyl-L-leucine.

4. Cytotoxic antibody conjugates according to claim 1 wherein the folic acid-antagonistic folic acid analogue is methotrexate, aminopterin or 10-ethyl-10-deaza-aminopterin.

5. A process for preparation of cytotoxic antibody conjugates of general formula (II)

View Dependent Claims (6, 7)

6. A process for preparation of cytotoxic antibody conjugates according to claim 5 wherein RCO in formulas (II) and (III) is represented by the formula (IV)

7. A process for preparation of cytotoxic antibody conjugates according to claim 6 wherein --NH--Y--CO--in general formula (IV) is a residual group of oligopeptide containing L-leucyl-L-alanyl-L-leucine.