IP Library › Granted Patent US 12,344,675
Granted Patent B2
US 12,344,675 · App. 18/927,497 · Granted Jul 1, 2025

Polypeptide comprising a single-domain antibody variable region that binds delta-like ligand 3 (DLL3) and method of use thereof to make a radionuclide complex

Inventors: Michael J. Abrams (Custer, WA); Emma Jane Cummins (Vancouver, CA); Adam Daniel Judge (Bainbridge Island, WA); Alexander Laurence Mandel (Vancouver, CA); Raja Solomon Viswas (Vancouver, CA)
Assignee: ABDERA THERAPEUTICS INC.
C07K16/3023A61K35/00A61K47/68035A61K47/6851A61K51/1054A61K51/1096A61K2121/00C07K2317/24C07K2317/569C07K2317/92
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Quick Facts
Patent No.
US 12,344,675
App. No.
18/927,497
Granted
Jul 1, 2025
Kind
B2
Abstract

Described herein are heavy chain antibodies that bind to DLL3 and immunoconjugates of DLL3 heavy chain antibodies useful for cancer therapy.

Claims (43)

1. A polypeptide comprising a single-domain antibody variable region that binds DLL3, wherein the single-domain antibody variable region comprises:

a heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 407, a heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 410, and a heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 413.

2. The polypeptide of claim 1 , wherein the single-domain antibody variable region comprises at least 90% sequence identity to any one of SEQ ID NOs: 401-406.

3. The polypeptide of claim 1 , wherein the single-domain antibody variable region comprises the sequence of any one of SEQ ID NOs: 401-406.

4. The polypeptide of claim 1 , wherein the single-domain antibody variable region binds to DLL3 with an affinity dissociation constant (K D ) of 0.1 nanomolar to 10 nanomolar.

5. The polypeptide of claim 1 , wherein the polypeptide comprises an immunoglobulin heavy chain constant region comprising an immunoglobulin C H 2 domain and an immunoglobulin C H 3 domain.

6. The polypeptide of claim 5 , wherein the immunoglobulin heavy chain constant region is an IgG1 isotype or an IgG4 isotype.

7. The polypeptide of claim 5 , wherein the immunoglobulin heavy chain constant region comprises an alteration to one or more amino acid residues relative to wild-type IgG1, and wherein the alteration reduces binding of the immunoglobulin heavy chain constant region to a neonatal Fc receptor (FcRn) relative to wild-type IgG1.

8. The polypeptide of claim 5 , wherein the immunoglobulin heavy chain constant region comprises an alteration to one or more amino acid residues relative to wild-type IgG1, and wherein the alteration reduces complement dependent cytotoxicity (CDC), antibody-dependent cell-cytotoxicity (ADCC), antibody-dependent cell-phagocytosis (ADCP), or a combination thereof relative to wild-type IgG1.

9. The polypeptide of claim 5 , wherein the immunoglobulin heavy chain constant region comprises a hinge region, and wherein the hinge region comprises a C220S alteration per EU numbering relative to wild-type IgG1.

10. An immunoconjugate comprising a polypeptide that binds to DLL3, wherein the polypeptide that binds to DLL3 is covalently linked to a linker-chelator moiety, or a radionuclide complex thereof, wherein:

the polypeptide comprises a single-domain antibody variable region comprising a heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 407, a heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 410, and a heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 413; and

the linker-chelator moiety or the radionuclide complex thereof is conjugated to the polypeptide.

11. The immunoconjugate of claim 10 , or the radionuclide complex thereof, wherein the linker-chelator moiety comprises:

1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA),

1,4,7-Tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (DO3A),

α-(2-Carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTAGA),

6,6′,6″,6″′-(((pyridine-2,6-diylbis(methylene))bis(azanetriyl))tetrakis(methylene))-tetrapicolinic acid (Py4 Pa),

2,2′,2″,2″′-(1,10-dioxa-4,7,13,16-tetraazacyclooctadecane-4,7,13,16-tetrayl)-tetraacetic acid (Crown),

6,6′-((1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diyl)bis(methylene))-dipicolinic acid,

1,4,7,10,13,16-hexaazacyclohexadecane-1,4,7,10,13,16-hexaacetic acid (HEHA),

6,6′-[(1R,2R)-1,2-Cyclohexanediylbis[[(carboxymethyl)imino]methylene]]bis[2-pyridinecarboxylic acid](CHXoctapa),

3,7-Diazabicyclo[3.3.1]nonane-1,5-dicarboxylic acid (Bispa), or

6,6′-(((oxybis(ethane-2,1-diyl))bis((carboxymethyl)azanediyl))-bis(methylene))-dipicolinic acid (Noneunpa).

12. The immunoconjugate of claim 10 , or the radionuclide complex thereof, wherein the linker-chelator moiety is:

13. The immunoconjugate of claim 12 , or the radionuclide complex thereof, wherein the linker-chelator moiety is

14. The immunoconjugate of claim 10 , or the radionuclide complex thereof, wherein the single-domain antibody variable region comprises at least 90% sequence identity to any one of SEQ ID NOs: 401-406.

15. The immunoconjugate of claim 10 , wherein the antibody variable region comprises the sequence of any one of SEQ ID NOs: 401-406.

16. The immunoconjugate of claim 10 , or the radionuclide complex thereof, wherein the single-domain antibody variable region binds to DLL3 with an affinity dissociation constant (K D ) of 0.1 nanomolar to 10 nanomolar.

17. The immunoconjugate of claim 10 , or the radionuclide complex thereof, wherein the polypeptide comprises an immunoglobulin heavy chain constant region comprising an immunoglobulin C H 2 domain and an immunoglobulin C H 3 domain.

18. The immunoconjugate of claim 17 , or the radionuclide complex thereof, wherein the immunoglobulin heavy chain constant region is an IgG1 isotype or an IgG4 isotype.

19. The immunoconjugate of claim 17 , or the radionuclide complex thereof, wherein the immunoglobulin heavy chain constant region comprises A310, Q435, or both A310 and A435 per EU numbering.

20. The immunoconjugate of claim 19 , or the radionuclide complex thereof, wherein the immunoglobulin heavy chain constant region comprises A234, E235, A237, S330, and S331 per EU numbering.

21. The immunoconjugate of claim 17 , or the radionuclide complex thereof, wherein the immunoglobulin heavy chain constant region comprises a hinge region, and wherein the hinge region comprises S220 per EU numbering.

22. The immunoconjugate of claim 10 , or the radionuclide complex thereof, wherein a lysine residue of the polypeptide is covalently linked via a thiourea to the para position of the benzyl of -p-Bn-DOTA formed from the isothiocyanate of -p-SCN-Bn-DOTA:

23. The immunoconjugate of claim 10 , or the radionuclide complex thereof, wherein the immunoconjugate has the following structure:

24. The immunoconjugate of claim 10 , or the radionuclide complex thereof, wherein the immunoconjugate has a chelator to polypeptide ratio of 3:1 to 5:1.

25. The immunoconjugate of claim 10 , or the radionuclide complex thereof, wherein the immunoconjugate comprises a linker-chelator radionuclide complex, and wherein the radionuclide is an alpha emitter, a beta emitter, or a gamma emitter.

26. The immunoconjugate of claim 25 , wherein the alpha emitter is 225-Ac.

27. A method of making a radionuclide complex of the immunoconjugate of claim 10 , the method comprising complexing the linker-chelator moiety of the immunoconjugate of claim 10 a radionuclide, thereby obtaining a radionuclide complex of the immunoconjugate.

28. The immunoconjugate of claim 10 , or the radionuclide complex thereof, wherein a lysine residue of the polypeptide is conjugated with one of the following linker-chelator moieties:

29. The immunoconjugate of claim 10 , or the radionuclide complex thereof, wherein the immunoconjugate has one of the following structures:

30. The method of claim 27 , wherein the radionuclide comprises 225-Ac.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 10, 2025
From: ABRAMS, MICHAEL J.; CUMMINS, EMMA JANE; JUDGE, ADAM DANIEL; MANDEL, ALEXANDER LAURENCE; VISWAS, RAJA SOLOMON
To: ABDERA THERAPEUTICS INC.
Reel/Frame 069814/0945 →
Continuity (4)
Continuation PCTUS2023072586 · Aug 21, 2023
Provisional Application 63477261 · Dec 27, 2022
Provisional Application 63373184 · Aug 22, 2022
Related Publication 20250051476A1 · Feb 13, 2025
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