NZ777971B2 - Multispecific antigen-binding molecules and uses thereof - Google Patents

Multispecific antigen-binding molecules and uses thereof Download PDF

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Publication number
NZ777971B2
NZ777971B2 NZ777971A NZ77797116A NZ777971B2 NZ 777971 B2 NZ777971 B2 NZ 777971B2 NZ 777971 A NZ777971 A NZ 777971A NZ 77797116 A NZ77797116 A NZ 77797116A NZ 777971 B2 NZ777971 B2 NZ 777971B2
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NZ
New Zealand
Prior art keywords
antibody
prlr
breast cancer
cancer cell
antigen
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NZ777971A
Other versions
NZ777971A (en
Inventor
Julian Andreev
Katherine Cygnar
Frank Delfino
Joel Martin
Nicholas Papadopoulos
Nithya Thambi
Gavin Thurston
Original Assignee
Regeneron Pharmaceuticals Inc
Filing date
Publication date
Application filed by Regeneron Pharmaceuticals Inc filed Critical Regeneron Pharmaceuticals Inc
Priority claimed from NZ737726A external-priority patent/NZ737726A/en
Publication of NZ777971A publication Critical patent/NZ777971A/en
Publication of NZ777971B2 publication Critical patent/NZ777971B2/en

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    • A61K2039/507—Comprising a combination of two or more separate antibodies
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    • C12N9/6454—Dibasic site splicing serine proteases, e.g. kexin (3.4.21.61); furin (3.4.21.75) and other proprotein convertases

Abstract

The present invention provides multispecific antigen-binding molecules and uses thereof. The multispecific antigen-binding molecules comprise a first antigen-binding domain that specifically binds a target molecule, and a second antigen-binding domain that specifically binds an internalizing effector protein. The multispecific antigen-binding molecules of the present invention can, in some embodiments, be bispecific antibodies that are capable of binding both a target molecule and an internalizing effector protein. In certain embodiments of the invention, the simultaneous binding of the target molecule and the internalizing effector protein by the multispecific antigen-binding molecule of the present invention results in the attenuation of the activity of the target molecule to a greater extent than the binding of the target molecule alone. In other embodiments of the invention, the target molecule is a tumor associated antigen, and the simultaneous binding of the tumor associated antigen and the internalizing effector protein by the multispecific antigen-binding molecule of the present invention causes or facilitates the targeted killing of tumor cells. In particular, the invention provides a bispecific PD-L1 and PRLR antibody that enhances degradation of PD-L1 from the breast cancer cells via PRLR assisted lysosome degradation, for treating breast cancer.

Claims (30)

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:
1. Use of an antibody that comprises (a) an antigen-binding fragment of an anti- programmed cell death protein ligand-1 (PD-L1) antibody and (b) an antigen-binding fragment of an anti-prolactin receptor (PRLR) antibody for the preparation of a medicament for forcing PD-L1, expressed on the surface of a breast cancer cell, to degrade in a lysosome, wherein the breast cancer cell is to be contacted with the antibody to physically link PD-L1 to PRLR, wherein the antibody binds to PD-L1 and PRLR on the same breast cancer cell; wherein PD-L1 is transported to a lysosome through its physical linkage to PRLR and degraded; and wherein the lysosomal degradation of PD-L1 through its physical linkage to PRLR is greater than the lysosomal degradation of PD-L1 not physically linked to PRLR.
2. The use of claim 1, wherein the antibody is a bispecific antibody.
3. The use of claim 1, wherein the breast cancer cell is in vivo.
4. The use of claim 2, wherein the bispecific antibody is an anti-PD-L1 x anti-PRLR bispecific antibody.
5. Use of an anti-PD-L1 bivalent monospecific antibody conjugated to a cytotoxic agent and an antibody that comprises (a) an antigen-binding fragment of an anti- PD-L1 antibody and (b) an antigen-binding fragment of an anti-PRLR antibody for the manufacture of a medicament for killing a breast cancer cell that expresses on its surface a PD-L1 molecule and a PRLR destroyer molecule, wherein: (i) the breast cancer cell is to be contacted with the anti-PD-L1 bivalent monospecific antibody conjugated to a cytotoxic agent, and (ii) the cell is to be contacted with the antibody that comprises (a) the antigen-binding fragment of the anti-PD-L1 antibody and (b) the antigen-binding fragment of the anti-PRLR antibody for simultaneous binding to PD-L1 and PRLR on the same cell, thereby physically linking PD-L1 to PRLR on the breast cancer cell of part (i), wherein the PD-L1 molecule and the cytotoxic agent are subsequently transported to a lysosome within the breast cancer cell through the physical linkage between the PD-L1 molecule and the PRLR destroyer molecule.
6. The use of claim 5, wherein the cytotoxic agent is a radioisotope, a toxin, or a drug.
7. The use of claim 6, wherein the toxin is a calicheamicin, an auristatin or a maytansine-based cytotoxin.
8. The use of claim 5, wherein the breast cancer cell is a T47D cell.
9. The use of claim 5, wherein the breast cancer cell is in vivo.
10. The use of claim 5, wherein cell-killing potency of the cytotoxic agent is enhanced by the presence of the antibody.
11. The use of claim 5, wherein the antibody that physically links PD-L1 with PRLR is a bispecific antibody.
12. The use of claim 5, wherein the killing inhibits the growth or promotes the regression of a tumor that comprises a breast cancer cell that expresses on its surface both a PD-L1 molecule and a PRLR destroyer molecule.
13. The use of claim 12, wherein the antibody that physically links PD-L1 with PRLR is an anti-PD-L1 x anti-PRLR bispecific antibody.
14. The use of claim 12, wherein the cytotoxic agent is a maytansinoid- based cytotoxin.
15. Use of an antibody cytotoxic agent conjugate that comprises (a) an antigen-binding fragment of an anti-PD-L1 antibody, (b) an antigen-binding fragment of an anti-PRLR antibody, and (c) a cytotoxic agent for the manufacture of a medicament for killing a breast cancer cell that expresses on its surface a PD-L1 molecule and a PRLR destroyer molecule, wherein the cell is to be contacted with the antibody cytotoxic agent conjugate to physically link PD-L1 to PRLR, wherein the PD-L1 molecule and the cytotoxic agent, through the physical linkage between the PD-L1 molecule and the PRLR destroyer molecule, are subsequently transported to a lysosome within the breast cancer cell.
16. The use of claim 15, wherein the cytotoxic agent is a radioisotope, a toxin, or a drug.
17. The use of claim 16, wherein the toxin is a calicheamicin, an auristatin, or a maytansine-based cytotoxin.
18. The use of claim 15, wherein the breast cancer cell is a T47D cell.
19. The use of claim 15, wherein the breast cancer cell is in vivo.
20. The use of claim 15, wherein cell-killing potency of the cytotoxic agent is enhanced by the presence of the antibody.
21. The use of claim 15, wherein the antibody cytotoxic agent conjugate comprises an anti-PD-L1 x anti-PRLR bispecific antibody.
22. The use of claim 15, wherein the killing inhibits the growth or promotes the regression of a tumor that comprises a breast cancer cell that expresses on its surface both a PD-L1 molecule and a PRLR destroyer molecule.
23. The use of claim 22, wherein the cytotoxic agent is a maytansinoid- based cytotoxin.
24. The use of claim 22, wherein the antibody cytotoxic agent conjugate comprises an anti-PD-L1 x anti-PRLR bispecific antibody.
25. Use of an antibody that comprises (a) an antigen-binding fragment of an anti-PD-L1 antibody and (b) an antigen-binding fragment of an anti-PRLR antibody for the manufacture of a medicament for forcing PD-L1, expressed on the surface of a breast cancer cell, to degrade in a lysosome, wherein the breast cancer cell is to be contacted with the antibody to physically link PD-L1 to PRLR, wherein the antibody binds to PD-L1 and PRLR on the same breast cancer cell; wherein PD-L1 is transported to a lysosome through its physical linkage to PRLR and degraded; and wherein, in the presence of an inhibitor of protein synthesis, at least about 40% of PD-L1 in the breast cancer cell is degraded after about 2 hours of contact with the antibody; and/or in the presence of an inhibitor of protein synthesis, at least about 80% of PD-L1 in the breast cancer cell is degraded after about 4 hours of contact with the antibody.
26. The use of claim 25, wherein the antibody is a bispecific antibody.
27. The use of claim 26, wherein the bispecific antibody is an anti-PD-L1 x anti-PRLR bispecific antibody.
28. Use of an antibody that comprises (a) an antigen-binding fragment of an anti-PD-L1 antibody and (b) an antigen-binding fragment of an anti-PRLR antibody for the manufacture of a medicament for forcing PD-L1, expressed on the surface of a breast cancer cell, to degrade in a lysosome, wherein the breast cancer cell is to be contacted with the antibody to physically link PD-L1 to PRLR, wherein the antibody binds to PD-L1 and PRLR on the same breast cancer cell; wherein PD-L1 is transported to a lysosome through its physical linkage to PRLR and degraded; and wherein degradation of PD-L1 is dependent on the dose of the antibody.
29. The use of claim 28, wherein the antibody is a bispecific antibody.
30. The use of claim 29, wherein the bispecific antibody is an anti-PD-L1 x anti-PRLR bispecific antibody.
NZ777971A 2016-07-06 Multispecific antigen-binding molecules and uses thereof NZ777971B2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201562188860P 2015-07-06 2015-07-06
US201662328900P 2016-04-28 2016-04-28
US201662347179P 2016-06-08 2016-06-08
NZ737726A NZ737726A (en) 2015-07-06 2016-07-06 Multispecific antigen-binding molecules and uses thereof

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NZ777971A NZ777971A (en) 2024-10-25
NZ777971B2 true NZ777971B2 (en) 2025-01-28

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