Triple-specific binding molecules for cancer and their use

Abstract

This provides an improved redirection-targeted T cell lysis (RTCC) technique. [Solution] This disclosure provides a conjugate comprising a multispecific binding molecule, a tripspecific binding molecule, and a pharmaceutical composition comprising a multispecific binding molecule and a conjugate, which specifically bind to a first tumor-associated antigen expressed in cancerous B cells, a second tumor-associated antigen expressed in cancerous B cells, and components of a human T cell receptor complex. This disclosure further provides a method for using the multispecific binding molecule to treat cancer expressing a tumor-associated antigen. This disclosure further also provides a method for producing the multispecific binding molecule by culturing recombinant host cells engineered to express the multispecific binding molecule and by culturing host cells under conditions in which the multispecific binding molecule is expressed.

Claims

1. A trivalent triple specificity binding molecule (TBM), (a) Specific to the first human tumor-associated antigen (TAA1) expressed in cancerous B cells. Antigen-binding module 1 (ABM1) that binds to, (b) Specific to the second human tumor-associated antigen (TAA2) expressed in cancerous B cells. Antigen-binding module 2 (ABM2) that binds to, (c) Antigen-binding modifier that specifically binds to components of the human T cell receptor (TCR) complex. Lure 3 (ABM3) and Includes, A first half-antibody containing scFv, Fc region and Fab, and a second half-antibody containing Fab and Fc region The first and second half-antibodies are found to be a combination of the first and second half-antibodies, and the two half-antibodies associate via their respective Fc regions. Furthermore, the Fc regions of the first and second half-antibodies form Fc domains, trivalent triple special Isomeric binding molecule (TBM).

2. TAA 1 and / or TAA 2 are found in cancerous B cells, which are B cell-derived plasma cells. The TBM described in claim 1 is expressed.

3. TAA1 and / or TAA2 are expressed in non-plasma cells, cancerous B cells. The TBM according to claim 1.

4. TAA 1 and TAA 2 are independent of each other, CD19, CD20, CD22, C D123, BCMA, CD33, CLL1, CD138, CS1, CD38, CD133 , FLT3, CD52, TNFRSF13C, TNFRSF13B, CXCR4, PD- L1, LY9, CD200, FCGR2B, CD21, CD23, CD24, CD40L T according to any one of claims 1 to 3, which is CD72, CD79a or CD79b. BM.

5. ABM1 is Fab, the TBM according to any one of claims 1 to 4.

6. The TBM according to claim 5, wherein ABM1 is a Fab heterodimer.

7. ABM2 is Fab, the TBM according to any one of claims 1 to 6.

8. The TBM according to claim 7, wherein ABM2 is a Fab heterodimer.

9. The constituent element of the human TCR complex is CD3, as described in any one of claims 1 to 8. TBM is featured.

10. The TBM according to claim 9, wherein ABM3 is scFv.

11. TBM and cytotoxic or cell proliferation inhibitory agent according to any one of claims 1 to 10 A conjugate that includes this.

12. The cytotoxic or cell proliferation inhibitory agent is conjugated to the TBM via a linker. The conjugate according to claim 11, which is provided.

13. TBM according to any one of claims 1 to 10 or condyloma according to claim 11 or 12 A pharmaceutical composition comprising a cereal and pharmaceutically acceptable excipients.

14. A TBM according to any one of claims 1 to 10 for treating B-cell malignancies, The conjugate described in claim 11 or 12, or the pharmaceutical composition described in claim 13.

15. The aforementioned B-cell malignant tumor includes cancerous B cells that express both TAA1 and TAA2. The TBM, conjugate, or pharmaceutical composition according to claim 14.

16. The aforementioned B-cell malignant tumor is a cancerous B-cell that expresses TAA1 but does not express TAA2. Claim 14 includes cancerous B cells that express TAA2 but not TAA1. The TBM, conjugate, or pharmaceutical composition described above.

17. The aforementioned B-cell malignant tumor is Hodgkin lymphoma, non-Hodgkin lymphoma, or multiple myeloma. The TBM, conjugate, or pharmaceutical composition according to any one of claims 14 to 16.

18. A TBM according to any one of claims 1 to 10 for treating an autoimmune disease, claim The conjugate described in item 11 or 12, or the pharmaceutical composition described in claim 13.

19. One or more nucleic acids encoding a TBM according to any one of claims 1 to 10.

20. Cells manipulated to express the TBM according to any one of claims 1 to 10.

21. Under the control of one or more promoters, T according to any one of claims 1 to 10 BM or one or more nucleic acid sequences encoding the conjugate described in claim 11 or 12 Cells transfected with one or more expression vectors.

22. A method for producing TBM, (a) Culture the cells according to claim 20 or 21 under conditions in which the TBM is expressed. To do, (b) Recovering the TBM from the cell culture A method that includes this.

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