Pharmaceutical compositions with resistance to soluble CEA
View Patent ↗The present disclosure relates to a bispecific single chain antibody which has a first binding domain specifically binding to human CD3, and a second binding domain specifically binding to human CEA, where the second binding domain comprises at least a part of the CDR-H3 or the complete CDR-H3 of murine monoclonal antibody A5B7, a pharmaceutical composition comprising the bispecific single chain antibody, and methods for the treatment of an epithelial tumor in a human with the pharmaceutical compositions containing the bispecific single chain antibody. Furthermore, processes for the production of the pharmaceutical compositions as well as medical/pharmaceutical uses for the specific bispecific single chain antibody molecules bearing specificities for the human CD3 antigen and the human CEA antigen are disclosed.
1. A bispecific single chain antibody which comprises:
(a) a first binding domain specifically binding to human CD3, and
(b) a second binding domain specifically binding to human CEA,
wherein said second binding domain comprises a variable light chain (V L ) region and a variable heavy chain (V H ) region,
wherein said V L region comprises:
a CDR-L1 having the amino acid sequence “TLRRGINVGAYSIY” (SEQ ID NO. 73);
a CDR-L2 having the amino acid sequence “YKSDSDKQQGS” (SEQ ID NO. 72); and
a CDR-L3 having the amino acid sequence “MIWHSGASAV” (SEQ ID NO. 71); and
wherein said V L region comprises:
a CDR-HI having the amino acid sequence “TYAMH” (SEQ ID NO. 70);
a CDR-H2 having the amino acid sequence “LISNDGSNKYYADSVKG” (SEQ ID NO. 69); and
a CDR-H3 having the amino acid sequence “DRGLRFYFDY” (SEQ ID NO. 66).
2. The bispecific single chain antibody of claim 1 , wherein said first binding domain specific for CD3 is located C-terminally to said second binding domain.
3. The bispecific single chain antibody of claim 1 , wherein said binding domains are arranged in the order VH CEA -VL CEA -VH CD3 -VL CD3 or VL CEA -VH CEA -VH CD3 -VL CD3 .
4. The bispecific single chain antibody of claim 1 , wherein the amino acid sequence of the VH region of the second binding domain specific for human CEA is SEQ ID NO: 58 or 62.
5. The bispecific single chain antibody of claim 1 , wherein the amino acid sequence of the VL region of the second binding domain specific for human CEA is SEQ ID NO: 64.
6. The bispecific single chain antibody of claim 1 , wherein the V regions of the second binding domain specific for CEA comprise
the VH region consisting of the amino acid sequence shown in SEQ ID NO: 58 and the VL region consisting of the amino acid sequence shown in SEQ ID NO: 64; or
the VH region consisting of the amino acid sequence shown in SEQ ID NO: 62 and the VL region consisting of the amino acid sequence shown in SEQ ID NO: 64.
7. The bispecific single chain antibody of claim 1 , wherein said bispecific single chain antibody comprises:
(a) an amino acid sequence set forth in SEQ ID NO: 24, 26, 40, 42, 44, 46, 126, 128, 134, or 136; or
(b) an amino acid sequence encoded by a nucleotide sequence as shown in SEQ ID NO: 23, 25, 27, 29, 39, 41, 43, 45, 125, 127, 133, or 135.
8. The bispecific single chain antibody of claim 1 , wherein at least one of said first or second binding domains is chimeric, humanized, CDR-grafted, and/or deimmunized or human.
9. The bispecific single chain antibody according to claim 1 , in a composition comprising a proteinaceous compound capable of providing an activation signal for immune effector cells.
10. A method for treating an epithelial tumor that expresses CEA in a subject in the need thereof, said method comprising the step of administering an effective amount of the bispecific single chain antibody of claim 1 .
11. The method of claim 10 , wherein said epithelial tumor is a gastrointestinal adenocarcinoma, a breast adenocarcinoma or a lung adenocarcinoma.
12. The method according to claim 11 , wherein said gastrointestinal adenocarcinoma is a colorectal adenocarcinoma, a pancreatic adenocarcinoma, an oesophageal adenocarcinoma, or a gastric adenocarcinoma.
13. The method according to claim 10 , wherein the subject in need thereof suffers from a progressive tumor, a late stage tumor, a high tumor load/burden, a metastatic tumor, or a CEA serum concentration higher than 100 ng/ml.
14. The method of claim 10 , wherein said bispecific single chain antibody is administered in combination with an additional drug.
15. The method of claim 14 , wherein said additional drug is a non-proteinaceous compound.
16. The bispecific single chain antibody of claim 1 , wherein said bispecific single chain antibody comprises a His-tag.
17. A composition comprising the bispecific single chain antibody of claim 1 .
18. The method of claim 15 , wherein the non-proteinaceous compound is administered non-simultaneously with the bispecific single chain antibody.
19. The method of claim 15 , wherein the non-proteinaceous compound is administered simultaneously with the bispecific single chain antibody.