Bi-and trispecific antibodies for the induction of anti-tumor immunity

• US 6,551,592 B2
• Filed: 09/03/1997
• Issued: 04/22/2003
• Est. Priority Date: 09/03/1996
• Status: Expired due to Term

• Current Assignee: Gsf-Forschungszentrum Fur Umwelt Und Gesundheit GmbH
• Original Assignee: Gsf-Forschungszentrum Fur Umwelt Und Gesundheit GmbH
• Inventors: Kolb, Hans-Jochem, Lindhofer, Horst, Thierfelder, Stefan
• Primary Examiner(s): Huff, Sheela
• Assistant Examiner(s): HELMS, LARRY RONALD
• Application Number:
  US08/923,852
• Publication Number:
  US 20020051780A1
• Time in Patent Office: 2,057 Days
• Field of Search: 424/136.1, 424/130.1, 424/138.1, 424/144.1, 530/387.1, 530/387.3, 530/388.1, 530/388.8, 530/388.85, 530/388.73, 530/388.23
• US Class Current: 424/136.1
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/2809 against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/30 from tumour cells
• CPC Class Codes: C07K 16/468 Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
• CPC Class Codes: C07K 2319/00 Fusion polypeptide

Abstract

According to the invention, a method is provided wherein intact bispecific or trispecific antibodies which at the same time bind to the T cell receptor complex of a T cell, to tumor-associated antigens on a tumor cell, and, via the Fc portion of the bispecific antibody, to Fc receptor-positive cells are used for the induction of an anti-tumour immunity in humans and animals.

Claims

1. A method of treatment of a human or animal subject suffering from a tumor disease consisting of administering to said subject an effective amount of an intact heterologous bispecific antibody having isotype combinations selected from the group consisting of:

rat-IgG2b/mouse-IgG2a,

rat-IgG2b/mouse-IgG2b,

rat-IgG2b/mouse-IgG3,

rat-IgG2b/human-IgG1,

rat-IgG2b/human-IgG2,

rat-IgG2b/human-IgG3(oriental allotype G3m(st)=binding to protein A),

rat-IgG2b/human-IgG4,

rat-IgG2b/rat-IgG2c,

mouse-IgG2a/human-IgG3(caucasian allotypes G3m(b+g)=no binding to protein A),

mouse-IgG2a/mouse-(VH-CH1,VL-CL)-human-IgG1-(hinge)-human-IgG3 Caucasian allotypes G3m(b+g)=no binding to protein A-(CH2-CH3),

mouse-IgG2a/rat-(VH-CH1,VL-CL)-human-IgG1-(hinge)-human-IgG3 caucasian allotypes G3m(b+g)=no binding to protein A-(CH2-CH3),

mouse-IgG2a/human-(VH-CH1,VL-CL)-human-IgG1-(hinge)-human IgG3 caucasian allotypes G3m(b+g)=no binding to protein A-(CH2-CH3),

mouse-(VH-CH1,VL-CL)-human-IgG1/rat-(VH-CH1,VL-CL)-human-IgG1-(hinge)-human-IgG3 caucasian allotypes G3m(b+g)=no binding to protein A-(CH2-CH3),

mouse-(VH-CH1,VL-CL)-human-IgG4/rat-(VH-CH1,VL-CL)-human-IgG4-(hinge)-human-IgG4(N-terminal region of CH2)-human-IgG3 caucasian allotypes G3m(b+g)=no binding to protein A (C-terminal region of CH2;

>

aa position

     251)-human-IgG3 caucasian allotypes G3m(b+g)=no binding to protein A (CH3),

rat-IgG2b/mouse-(VH-CH1,VL-CL)-human-IgG1-(hinge-CH2-CH3),

rat-IgG2b/mouse-(VH-CH1,VL-CL)-human-IgG3-(hinge-CH2-CH3, oriental allotype),

rat-IgG2b/mouse-(VH-CH1,VL-CL)-human-IgG4-(hinge-CH2-CH3)human-IgG1/human-(VH-CH1,VL-CL)-human-IgG1-(hinge)-human-IgG3 caucasian allotypes G3m(b+g)=no binding to protein A-(CH2-CH3),

human-IgG1/rat-(VH-CH1,VL-CL)-human-IgG1-(hinge)-human-IgG4(N-terminal region of CH2)-human-IgG3 caucasian allotypes G3m(b+g)=no binding to protein A (C-terminal region of CH2;

>

aa position

     251)-human-IgG3 Caucasian allotypes G3m(b+g)=no binding to protein A (CH3),

human-IgG1/mouse-(VH-CH1,VL-CL)-human-IgG1-(hinge)-human-IgG4(N-terminal region of CH2)-human-IgG3 Caucasian allotypes G3m(b+g)=no binding to protein A (C-terminal region of CH2;

>

aa position

     251)-human-IgG3 Caucasian allotypes G3m(b+g)=no binding to protein A (CH3),

human-IgG1/rat-(VH-CH1,VL-CL)-human-IgG1-(hinge)-human-IgG2(N-terminal region of CH2)-human-IgG3 caucasian allotypes G3m(b+g)=no binding to protein A (C-terminal region of CH2;

>

aa position

     251)-human-IgG3 caucasian allotypes G3m(b+g)=no binding to protein A (CH3),

human-IgG1/mouse-(VH-CH1,VL-CL)-human-IgG1-(hinge)-human-IgG2(N-terminal region of CH2)-human-IgG3 caucasian allotypes G3m(b+g)=no binding to protein A (C-terminal region of CH2;

>

aa position

     251)-human-IgG3 Caucasian allotypes G3m(b+g)=no binding to protein A (CH3),

human-IgG1/rat-(VH-CH1,VL-CL)-human-IgG1-(hinge)-human-IgG3 caucasian allotypes G3m(b+g)=no binding to protein A-(CH2-CH3),

human-IgG1/mouse-(VH-CH1,VL-CL)-human-IgG1-(hinge)-human-IgG3 caucasian allotypes G3m(b+g)=no binding to protein A-(CH2-CH3),

human-IgG2/human-(VH-CH1,VL-CL)-human-IgG2-(hinge)-human-IgG3 caucasian allotypes G3m(b+g)=no binding to protein A-(CH2-CH3),

human-IgG4/human-(VH-CH1,VL-CL)-human-IgG4-(hinge)-human-IgG3 caucasian allotypes G3m(b+g)=no binding to protein A-(CH2-CH3),

human-IgG4/human-(VH-CH1,VL-CL)-human-IgG4-(hinge)-human-IgG4(N-terminal region of CH2)-human-IgG3 Caucasian allotypes G3m(b+g)=no binding to protein A (C-terminal region of CH2;

>

aa position

     251)-human-IgG3 caucasian allotypes G3m(b+g)=no binding to protein A (CH3),

mouse-IgG2b/rat-(VH-CH1,VL-CL)-human-IgG1-(hinge)-human-IgG3 caucasian allotypes G3m(b+g)=no binding to protein A-(CH2-CH3),

mouse-IgG2b/human-(VH-CH1,VL-CL)-human-IgG1-(hinge)-human-IgG3 caucasian allotypes G3m(b+g)=no binding to protein A-(CH2-CH3), and

mouse-IgG2b/mouse-(VH-CH1,VL-CL)-human-IgG1-(hinge)-human-IgG3 caucasian allotypes G3m(b+g)=no binding to protein A-(CH2-CH3);

wherein said antibody provides the following properties and effects;

(a) binding to a T cell and activating said T cell;

(b) binding to tumor-associated antigens on a tumor cell;

(c) binding, through its Fc portion to the Fc receptor of Fc receptor-positive cells;

(d) activation of said Fc receptor-positive cell by said binding of said antibodies to the Fc receptor-positive cell and, thereby initiating or increasing the expression of cytokines and/or co-stimulatory molecules;

(e) inducing a physiological activation of the T cell by a member selected from the group consisting of co-stimulatory molecules and cytokines, this activation being indicated by up-regulation of activation markers, killing of the tumor cell, T cell proliferation or a combination thereof,

inducing anti-tumor immunity.

2. Method according to claim 1, wherein said antibody further is able to reactivate tumor-specific T cells, which T cells are in a state of anergy.

3. Method according to claim 2, wherein said antibody further is able to activate the tumor-specific T cells after binding to the bispecific antibody as described in (e), wherein said tumor-specific T cells recognize a tumor-specific peptide presented on the tumor cells by a member selected from the group consisting of MHC class I, MHC class II, and a combination thereof via their T cell receptor.

4. Method according to claim 1, wherein said antibody is able to induce tumor-binding complement-binding antibodies and, thereby, to induce a humoral immune response.

5. Method according to claim 1, wherein said antibody binds to the T cell via a member selected from the group consisting of CD3, CD2, CD5, CD28, and CD44.

6. Method according to claim 1, wherein said antibody is able to bind to Fc receptor-positive cells having a Fcγ

receptor I, II, or III.

7. Method according to claim 6, wherein said antibody is able to bind to a member selected from the group consisting of monocytes, macrophages, and dendritic cells that are Fcγ

receptor I-positive cells.

8. Method according to claim 1, wherein expression of the co-stimulatory molecules is selected from the group consisting of CD40, CD80, CD86, ICAM-1, and LFA-3 or the secretion of cytokines is initiated or increased by the Fc receptor-positive cell.

9. Method according to claim 8, wherein the cytokines are members selected from the group consisting of IL-1, IL-2, IL-4, IL-6, IL-8, IL-12, and TNF-α

.

10. Method according to claim 1, wherein said binding to a T cell takes place via the T cell receptor complex of the T cell.

11. Method according to claim 1, wherein said antibody is a bi-specific antibody selected from the group consisting of anti-CD3 X anti-tumor-associated antigen antibody, anti-CD2 X anti-tumor-associated antigen antibody, anti-CD5 X anti-tumor-associated antigen antibody, anti-CD28 X anti-tumor-associated antigen antibody, and anti-CD44 X anti-tumor-associated antigen antibody.

12. Method according to claim 1, wherein said antibody is a heterologous rat/mouse bi-specific antibody.

13. Method according to claim 1, wherein said antibody is administered in an amount of 5 μ

g-10 mg/subject when said subject is in a minimal residual disease (MRD) situation.