Bispecific molecules that are immunoreactive with immune effector cells of a companion animal that express an activating receptor and cells that express B7-H3 and uses thereof
The present invention relates to bispecific molecules that are immunoreactive to an activating receptor of a companion animal immune effector cell and to B7-H3, and to the use of such bispecific molecules in the treatment of cancer in companion animals.
1. A bispecific molecule comprising:
(A) a first epitope-binding domain, said first epitope-binding domain being capable of binding to an epitope of CD3 expressed on the surface of an immune effector cell of a companion animal, wherein said companion animal is a canine animal or a feline animal, and wherein said first epitope-binding domain comprises the amino acid sequences of:
(1) CDR 1 (SEQ ID NO:93), CDR 2 (SEQ ID NO:95) and CDR 3 (SEQ ID NO:97) of the light chain of K9CD3-1 and CDR 1 (SEQ ID NO:101), CDR 2 (SEQ ID NO:103) and CDR 3 (SEQ ID NO:105) of the heavy chain of K9CD3-1;
or
(2) CDR 1 (SEQ ID NO:109), CDR 2 (SEQ ID NO:111) and CDR 3 (SEQ ID NO:113) of the light chain of K9CD3-2 and CDR 1 (SEQ ID NO:117), CDR 2 (SEQ ID NO:119) and CDR 3 (SEQ ID NO:121) of the heavy chain of K9CD3-2; and
(B) a second epitope-binding domain, said second epitope-binding domain being capable of binding to an epitope of a cancer cell of said companion animal that expresses B7-H3.
2. The bispecific molecule of claim 1 , wherein the companion animal is a canine animal.
3. The bispecific molecule of claim 1 , wherein said immune effector cell is a T-cell.
4. The bispecific molecule of claim 1 , wherein said bispecific molecule is a diabody molecule.
5. The bispecific molecule of claim 1 , wherein said bispecific molecule further comprises an Fc region, and/or an albumin-binding domain.
6. The bispecific molecule of claim 1 , wherein said second epitope-binding domain comprises a variable domain that comprises:
(A) CDR 1 (SEQ ID NO:25), CDR 2 (SEQ ID NO:27) and CDR 3 (SEQ ID NO:29) of the light chain of BRCA69D and CDR 1 (SEQ ID NO:33), CDR 2 (SEQ ID NO:35) and CDR 3 (SEQ ID NO:37) of the heavy chain of BRCA69D;
or
(B) CDR 1 (SEQ ID NO:9), CDR 2 (SEQ ID NO:11) and CDR 3 (SEQ ID NO:13) of the light chain of BRCA84D and CDR 1 (SEQ ID NO:17), CDR 2 (SEQ ID NO:19) and CDR 3 (SEQ ID NO:21) of the heavy chain of BRCA84D.
7. A method of treating cancer in a companion animal which comprises administering to said companion animal a bispecific molecule, wherein said bispecific molecule comprises:
(A) a first epitope-binding domain, said first epitope-binding domain being capable of binding to an epitope of CD3 expressed on the surface of an immune effector cell of a companion animal, wherein said companion animal is a canine animal or a feline animal, and wherein said first epitope-binding domain comprises the amino acid sequences of:
(1) CDR 1 (SEQ ID NO:93), CDR 2 (SEQ ID NO:95) and CDR 3 (SEQ ID NO:97) of the light chain of K9CD3-1 and CDR 1 (SEQ ID NO:101), CDR 2 (SEQ ID NO:103) and CDR 3 (SEQ ID NO:105) of the heavy chain of K9CD3-1;
or
(2) CDR 1 (SEQ ID NO:109), CDR 2 (SEQ ID NO:111) and CDR 3 (SEQ ID NO:113) of the light chain of K9CD3-2 and CDR 1 (SEQ ID NO:117), CDR 2 (SEQ ID NO:119) and CDR 3 (SEQ ID NO:121) of the heavy chain of K9CD3-2; and
(B) a second epitope-binding domain, said second epitope-binding domain being capable of binding to an epitope of a cancer cell of said companion animal that expresses B7-H3;
wherein said bispecific molecule is administered to said companion animal in an amount effective to cause said molecule to bind to both said immune effector cell and said cancer cell, to thereby co-localize said cells and facilitate the killing of said cancer cell by said immune effector cell.
8. The method of claim 7 , wherein said companion animal is a canine animal.
9. The method of claim 7 , wherein said immune effector cell is a T-cell.
10. The method of claim 7 , wherein said bispecific molecule is a diabody molecule.
11. The method of claim 7 , wherein said bispecific molecule further comprises an Fc region and/or an albumin-binding domain.
12. The method of claim 7 , wherein said second epitope-binding domain comprises a variable domain that comprises:
(A) CDR 1 (SEQ ID NO:25), CDR 2 (SEQ ID NO:27) and CDR 3 (SEQ ID NO:29) of the light chain of BRCA69D and CDR 1 (SEQ ID NO:33), CDR 2 (SEQ ID NO:35) and CDR 3 (SEQ ID NO:37) of the heavy chain of BRCA69D;
or
(B) CDR 1 (SEQ ID NO:9), CDR 2 (SEQ ID NO:11) and CDR 3 (SEQ ID NO:13) of the light chain of BRCA84D and CDR 1 (SEQ ID NO:17), CDR 2 (SEQ ID NO:19) and CDR 3 (SEQ ID NO:21) of the heavy chain of BRCA84D.
13. The method of claim 7 , wherein the cancer is selected from the group consisting of canine histiocytic sarcoma, canine hemangiosarcoma, canine malignant melanoma, canine mast cell tumor, canine osteosarcoma, canine thyroid carcinoma, canine transitional cell carcinoma, canine squamous cell carcinoma, feline fibrosarcoma, feline mammary sarcoma, and feline squamous cell carcinoma.
14. A K9CD3xB7-H3 bispecific molecule comprising SEQ ID NO:154, SEQ ID NO:156 and SEQ ID NO:158.