PYRROLOBENZODIAZEPINE-ANTIBODY CONJUGATES AND USES THEREOF

1 . A conjugate of formula (I):

Ab-(DL) p   (I)

wherein:

Ab is an antibody that binds to CD45; and DL is:

2 . The conjugate according to any claim 1 , wherein p is 1 to 4.

3 . The conjugate according to claim 1 , wherein the antibody comprises a VH domain comprising a VH CDR3 with the amino acid sequence of SEQ ID NO. 5., a VH CDR2 with the amino acid sequence of SEQ ID NO. 4, and a VH CDR1 with the amino acid sequence of SEQ ID NO. 3.

4 . The conjugate according to claim 1 , wherein the antibody comprises a VH domain having the sequence of SEQ ID NO. 1.

5 . The conjugate according to claim 3 , wherein the antibody comprises a VL domain comprising a VL CDR3 with the amino acid sequence of SEQ ID NO. 8., a VL CDR2 with the amino acid sequence of SEQ ID NO. 7, and a VL CDR1 with the amino acid sequence of SEQ ID NO. 6.

6 . The conjugate according to claim 4 , wherein the antibody comprises a VL domain having the sequence of SEQ ID NO. 2.

7 . The conjugate according to claim 1 , wherein the antibody comprises a VH domain comprising a VH CDR3 with the amino acid sequence of SEQ ID NO. 15., a VH CDR2 with the amino acid sequence of SEQ ID NO. 14, and a VH CDR1 with the amino acid sequence of SEQ ID NO. 13.

8 . The conjugate according to claim 1 , wherein the antibody comprises a VH domain having the sequence of SEQ ID NO. 11.

9 . The conjugate according to claim 7 , wherein the antibody comprises a VL domain comprising a VL CDR3 with the amino acid sequence of SEQ ID NO. 18., a VL CDR2 with the amino acid sequence of SEQ ID NO. 17, and a VL CDR1 with the amino acid sequence of SEQ ID NO. 16.

10 . The conjugate according to claim 8 , wherein the antibody comprises a VL domain having the sequence of SEQ ID NO. 12.

11 . The conjugate according to claim 1 , wherein the antibody comprises a first antigen binding domain and a second antigen binding domain, wherein:

the first antigen binding domain comprises a VH domain comprising a VH CDR3 with the amino acid sequence of SEQ ID NO. 5., a VH CDR2 with the amino acid sequence of SEQ ID NO. 4, and a VH CDR1 with the amino acid sequence of SEQ ID NO. 3 and/or a VL domain comprising a VL CDR3 with the amino acid sequence of SEQ ID NO. 8., a VL CDR2 with the amino acid sequence of SEQ ID NO. 7, and a VL CDR1 with the amino acid sequence of SEQ ID NO. 6; and

the second antigen binding domain comprises a VH domain comprising a VH CDR3 with the amino acid sequence of SEQ ID NO. 15., a VH CDR2 with the amino acid sequence of SEQ ID NO. 14, and a VH CDR1 with the amino acid sequence of SEQ ID NO. 13 and/or a VL domain comprising a VL CDR3 with the amino acid sequence of SEQ ID NO. 18., a VL CDR2 with the amino acid sequence of SEQ ID NO. 17, and a VL CDR1 with the amino acid sequence of SEQ ID NO. 16.

12 . The conjugate according to claim 1 , wherein the antibody in an intact antibody.

13 . The conjugate according to claim 1 , wherein said antibody is non-human.

14 . The conjugate according to claim 1 , wherein the antibody is a rat antibody such as a rat IgG2b.

15 . A method of treating cancer, the method comprising administering an effective amount of the conjugate according claim 1 to a subject in need thereof.

16 . A pharmaceutical composition comprising a first conjugate of formula (I), a second conjugate of formula (I), and optionally a pharmaceutically acceptable diluent, carrier or excipient,

(

I

)

⁢

:

⁢

Ab

-

(

DL

)

p

(

I

)

wherein:

Ab is an antibody that binds to CD45; and DL is:

and wherein:

(a) the antibody of the first conjugate comprises a VH domain comprising a VH CDR3 with the amino acid sequence of SEQ ID NO. 5., a VH CDR2 with the amino acid sequence of SEQ ID NO. 4, and a VH CDR1 with the amino acid sequence of SEQ ID NO. 3 and a VL domain comprising a VL CDR3 with the amino acid sequence of SEQ ID NO. 8., a VL CDR2 with the amino acid sequence of SEQ ID NO. 7, and a VL CDR1 with the amino acid sequence of SEQ ID NO. 6; and

(b) the antibody of the second conjugate comprises a VH domain comprising a VH CDR3 with the amino acid sequence of SEQ ID NO. 15., a VH CDR2 with the amino acid sequence of SEQ ID NO. 14, and a VH CDR1 with the amino acid sequence of SEQ ID NO. 13 and a VL domain comprising a VL CDR3 with the amino acid sequence of SEQ ID NO. 18., a VL CDR2 with the amino acid sequence of SEQ ID NO. 17, and a VL CDR1 with the amino acid sequence of SEQ ID NO. 16.

17 . A method of treating haematological cancer, the method comprising administering the conjugate according to claim 1 to a subject in need thereof.

18 . The method of claim 17 , wherein the haematological cancer is selected from the group consisting of: acute myeloid leukaemia, acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, chronic myeloid leukaemia, myelodysplasia, multiple myeloma, non-Hodgkin's lymphoma and Hodgkin's disease.

19 . A method of preparing a subject for transplantation of haematopoietic stem cells, the method comprising administering the conjugate according to claim 1 to the subject.

20 . The method of claim 19 wherein the preparing for transplantation of haematopoietic stem cells comprises conditioning the subject for engraftment of haematopoietic stem cells.

21 . The method of claim 19 , wherein the haematopoietic stem cells are allogeneic.

22 . The method of claim 21 , wherein said transplantation of haematopoietic stem cells is for treating a malignant disease or disorder, optionally selected from the group consisting of: acute myeloid leukaemia, acute lymphoblastic leukaemia, chronic myeloid leukaemia, chronic lymphocytic leukaemia, myelodysplasia, myeloproliferative diseases, non-Hodgkin's lymphoma and Hodgkin's disease.

23 . The method of claim 21 , wherein said transplantation of haematopoietic stem cells is for treating a non-malignant disease or disorder, optionally selected from the group consisting of: severe aplastic anaemia, a bone marrow failure disorder, a primary immunodeficiency, a haemoglobinopathy, primary haemophagocytic lymphohistiocytosis and a genetic metabolic disease.

24 . The method of claim 21 , wherein said transplantation of haematopoietic stem cells is for treating:

(i) a bone marrow failure disorder selected from Fanconi anaemia, dyskeratosis congenital, Schwachmann-Diamond Syndrome;

(ii) a primary immunodeficiency selected from SCID, chronic granulomatous disease, Wiskott-Aldrich syndrome, CD40 ligand deficiency, XLP, MHC Class II deficiency;

(i) a haemoglobinopathy selected from sickle cell disease, β-thalassaemia major; or

(ii) a genetic metabolic disease selected from Hurler syndrome, X-linked adrenoleukodystrophy and osteopetrosis.

25 . The method of claim 19 , wherein the haematopoietic stem cells are autologous.

26 . The method of claim 25 , wherein said transplantation of haematopoietic stem cells is for treating a malignant disease or disorder, optionally selected from the group consisting of: multiple myeloma, non-Hodgkin's lymphoma, Hodgkin's disease.

27 . The claim of method 25 , wherein said transplantation of haematopoietic stem cells is for treating an autoimmune disease or disorder, optionally selected from the group consisting of: multiple sclerosis, systemic sclerosis and systemic lupus erythematosus.

28 . The method of claim 19 , wherein the haematopoietic stem cells are genetically-modified autologous haematopoietic stem cells.

29 . The method of claim 19 , wherein said transplantation of haematopoietic stem cells is for gene therapy;

optionally wherein the gene therapy is for treating a genetic haematological disease or disorder, a primary immunodeficiency or a genetic metabolic disorder, such as:

(i) a genetic haematological disease or disorder selected from a haemoglobinopathy, a transfusion dependent haemoglobinopathy, sickle cell disease, β-thalassemia major, Fanconi anaemia, and primary HLH;

(ii) a primary immunodeficiency selected from SCID, chronic granulomatous disease, and Wiskott-Aldrich syndrome; or

(iii) a genetic metabolic disorder selected from Hurler's syndrome, X-adrenoleukodystrophy, and metachromatic leukodystrophy.

30 . A method of engrafting stem cells in a subject, the method comprising:

(a) administering to the subject an effective amount of the conjugate according to claim 1 ; and

(b) administering a stem cell population to the target tissue of the subject, wherein the administered stem cell population engrafts in the target tissue of the subject.