Use of Anti-ceacam5 immunoconjugates for treating neuroendocrine cancers expressing ceacam5

HK40135731APending Publication Date: 2026-07-31SANOFI SA(FR)
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Patent Information

Application Number
HK62026124133
Authority / Receiving Office
HK · HK
Patent Type
Applications
Current Assignee / Owner
Priority Date
2023-03-01
Filing Date
2026-05-29
Publication Date
2026-07-31

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Abstract

The present disclosure provides methods of treating neuroendocrine cancers using immunoconjugates comprising an antibody that specifically binds hCEACAM5, in particular hCEACAM5.
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Description

Use of anti-CEACAM5 immunoconjugates for the treatment of neuroendocrine cancers expressing CEACAM5 (Summary) This disclosure provides a method for treating neuroendocrine cancers using immunoconjugates comprising antibodies that specifically bind to hCEACAM5, particularly hCEACAM5.

Claims

CLAIMS1. An immunoconjugate comprising an antibody or an antigen-binding fragment thereof, for use in treating a cancer selected from neuroendocrine cancers expressing hCEACAM5, in a subject in need thereof, wherein said antibody or antigen-binding fragment thereof specifically binds hCEACAM5, and wherein said antibody or antigen-binding fragment thereof is conjugated or linked to at least one growth inhibitory agent, wherein said growth inhibitory agent is not a topoisomerase I inhibitor.

2. The immunoconjugate for use according to claim 1 , wherein said antibody or antigenbinding fragment thereof comprises a VH and a VL domain, wherein the VH domain comprises the three complementarity-determining regions (CDRs) HCDR1, HCDR2 and HCDR3 and wherein the VL domain comprises the three CDRs: LCDR1, LCDR2 and LCDR3, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 3 (GFVFSSYD); the HCDR2 comprises the amino acid sequence of SEQ ID NO: 4 (ISSGGGIT); the HCDR3 comprises the amino acid sequence of SEQ ID NO: 5 (AAHYFGSSGPFAY); and the LCDR1 comprises the amino acid sequence of SEQ ID NO: 6 (ENIFSY); the LCDR2 comprises the amino acid sequence of NTR; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 7 (QHHYGTPFT).

3. An antibody, or an antigen-binding fragment thereof, or an immunoconjugate comprising said antibody or said antigen-binding fragment thereof, for use in treating a cancer selected from neuroendocrine cancers expressing hCEACAM5, in a subject in need thereof, wherein said antibody or antigen-binding fragment thereof specifically binds hCEACAM5, wherein said antibody or antigen-binding fragment thereof comprises a VH and a VL domain, wherein the VH domain comprises the three complementarity-determining regions (CDRs) HCDR1, HCDR2 and HCDR3 and wherein the VL domain comprises the three CDRs: LCDR1, LCDR2 and LCDR3, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 3 (GFVFSSYD); the HCDR2 comprises the amino acid sequence of SEQ ID NO: 4 (ISSGGGIT); the HCDR3 comprises the amino acid sequence of SEQ ID NO: 5 (AAHYFGSSGPFAY); andthe LCDR1 comprises the amino acid sequence of SEQ ID NO: 6 (ENIFSY); the LCDR2 comprises the amino acid sequence of NTR; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:7 (QHHYGTPFT), wherein said neuroendocrine cancer is not a neuroendocrine small cell lung carcinoma (SCLC).

4. An antibody, or an antigen-binding fragment thereof, or an immunoconjugate comprising said antibody or said antigen-binding fragment, for use in treating a cancer selected from neuroendocrine cancers expressing hCEACAM5 in a subject in need thereof, wherein the antibody specifically binds hCEACAM5 and wherein the antibody, or the antigen-binding fragment thereof, comprises a VH and a VL domain, wherein the VH domain comprises the three complementaritydetermining regions (CDRs) HCDR1, HCDR2 and HCDR3 and wherein the VL domain comprises the three CDRs: LCDR1, LCDR2 and LCDR3, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 3 (GFVFSSYD); the HCDR2 comprises the amino acid sequence of SEQ ID NO: 4 (ISSGGGIT); the HCDR3 comprises the amino acid sequence of SEQ ID NO: 5 (AAHYFGSSGPFAY); and the LCDR1 comprises the amino acid sequence of SEQ ID NO: 6 (ENIFSY); the LCDR2 comprises the amino acid sequence of NTR; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 7 (QHHYGTPFT).

5. The antibody or immunoconjugate for use according to any one of claims 1 -4, wherein the cancer is selected from neuroendocrine tumors (NET), neuroendocrine carcinomas (NEC), Mixed Neuroendocrine-Non-Neuroendocrine Neoplasma (MiNEN), Pheochromocytoma and Medullary thyroid carcinoma (MTC).

6. The antibody or immunoconjugate for use according to any one of claims 1, 2 and 4, wherein the cancer is selected from neuroendocrine cancers of:- the gastrointestinal and pancreatobiliary tract, such as neuroendocrine cancers of the digestive tract in particular the oesophagus, the stomach, the pancreas, the liver, the small intestine and large intestine or the anal region, or such as neuroendocrine cancers of the urinary tract, in particular the bladder;- the upper aerodigestive tract and salivary glands, such as neuroendocrine cancers of the lung, in particular a small cell lung cancer, and such as neuroendocrine cancers of the thymus;- the thyroid, such as medullary thyroid carcinoma (MTC);- the adrenal gland, such as pheochromocytoma;- the skin, such as Merkel cell carcinoma (MCC);- the female reproductive organs, such as of the endometrium, the uterine cervix or the ovary;- the male reproductive organs, such as of the prostate or the testis, in particular the testis, and- the head and neck.

7. The antibody or immunoconjugate for use according to any one of claims 1, 2 and 4, wherein the cancer is selected from neuroendocrine cancers of the oesophagus, the stomach, the small intestine and the large intestine, the anal region, the pancreas, the bladder, the lung, the female reproductive organs, the male reproductive organs, the thyroid and the head and neck.

8. The antibody or immunoconjugate for use according to any one of claims 1, 2 and 4, wherein the cancer is a neuroendocrine cancer of the lung, in particular a neuroendocrine small cell lung cancer, or a neuroendocrine cancer of the male reproductive organs, in particular a neuroendocrine prostate cancer.

9. The antibody or immunoconjugate for use according to any one of claims 1, 2 and 4- 8, wherein the cancer is a neuroendocrine small cell lung cancer.

10. The antibody or immunoconjugate for use according to any one of claims 1, 2 and 4- 8, wherein the cancer is neuroendocrine prostate cancer.

11. The antibody or immunoconjugate for use according to any one of the preceding claims, wherein the subject is a moderate or high carcinoembryonic antigen-related cell adhesion molecule expresser.

12. The antibody or immunoconjugate for use according to claim 11, wherein the subject is a moderate CEACAM5 expresser, that is a subject who has a CEACAM5 expression consisting of 2+ or 3+ intensity, measured by hCEACAM5 immunohistochemistry, in at least 1 % of the tumor cell population or consisting of 1+ intensity in at least 50 % of the tumor cell population.

13. The antibody or immunoconjugate for use according to claim 11, wherein the subject is a high CEACAM5 expresser, that is a subject who has a CEACAM5 expression consisting of 2+ or 3+ intensity, measured by hCEACAM5 immunohistochemistry, in over 50% of the tumor cell population.

14. The antibody or immunoconjugate for use according to any one of claims 2 to 13, wherein the VH domain comprises SEQ ID NO: 1:EVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYISSG GGITYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHYFGSSGPFAYWG QGTLVTVSS.

15. The antibody or immunoconjugate for use according to any one of the preceding claims, comprising a heavy chain comprising SEQ ID NO: 8:EVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYISSG GGITYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHYFGSSGPFAYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG.

16. The antibody or immunoconjugate for use according to any one of claims 2 to 15, wherein the VL domain comprises SEQ ID NO: 2:DIQMTQSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSPKLLVYNTRTLA EGVPSRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGTPFTFGSGTKLEIK.

17. The antibody or immunoconjugate for use according to any one of claims 2 to 16, comprising a light chain comprising SEQ ID NO: 9:DIQMTQSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSPKLLVYNTRTLA EGVPSRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGTPFTFGSGTKLEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC.

18. The immunoconjugate comprising the antibody, for use according to any one of claims 3 to 17, wherein the antibody is conjugated or linked to at least one growth inhibitory agent, in particular to at least one growth inhibitor that is a cytotoxic agent.

19. The immunoconjugate for use according to claim 18, wherein said growth inhibitory agent is selected from the group consisting of chemotherapeutic agents, enzymes, antibiotics, and toxins such as small molecule toxins or enzymatically active toxins, taxoids, vincas, taxanes, maytansinoid or maytansinoid analogs, tomaymycin or pyrrolobenzodiazepine derivatives, cryptophycin derivatives, leptomycin derivatives, auristatin or dolastatin analogs, prodrugs, topoisomerase inhibitors, DNA alkylating agents, anti-tubulin agents, and CC-1065 or CC-1065 analogs.

20. The immunoconjugate for use according to claim 18, wherein said growth inhibitor is not a topoisomerase I inhibitor.

21. The immunoconjugate for use according to any one of claims 1-2 and 5-20, wherein said growth inhibitory agent is (N2’-de acetyl -A' ’-(3 -mercapto- l-oxopropyl)-maytansine) (DM1) or N2’-deacetyl -A2’-(4-methyl-4-mercapto- 1 -oxopentylj-maytansine (DM4).

22. The immunoconjugate for use according to any one of claims 1-2 and 5-21, wherein the antibody is covalently attached via a cleavable or non-cleavable linker to the at least one growth inhibitory agent, in particular via a linker selected from the group consisting of N-succinimidyl pyridyldithiobutyrate (SPDB), 4-(Pyridin-2-yldisulfanyl)-2-sulfo-butyric acid (sulfo-SPDB), and succinimidyl (N-maleimidomethyl) cyclohexane- 1 -carboxylate (SMCC).

23. The immunoconjugate for use according to any one of claims 1-22, comprising a hCEACAM5-antibody, which comprises a heavy chain consisting of SEQ ID NO: 8 and a light chain consisting of SEQ ID NO: 9, and which is covalently linked to N2’-deacetyl -N2’(4-methyl-4-mercapto- l-oxopentyl)-maytansine (DM4) via N-succinimidyl pyridyldithiobutyrate (SPDB).

24. The immunoconjugate for use according to any one of claims 1-23, wherein the immunoconjugate is Tusamitamab ravtansine.

25. The antibody or immunoconjugate for use according to any one of claims 1-24, wherein the antibody or immunoconjugate is administered at a dose level of 5, 10, 20, 30, 40, 60, 80, 100, 120, 150, 180, or 210 mg / m2based on the body surface area of the subject.

26. The antibody or immunoconjugate for use according to any one of claims 1-25, wherein the antibody or immunoconjugate is administered every 2 weeks, or every 3 weeks.

27. The antibody or immunoconjugate for use according to any of claims 1-26, wherein the antibody or immunoconjugate is administered at a dose level of 100 mg / m2based on the body surface area of the subject every 2 weeks.

28. The antibody or immunoconjugate for use according to any one of claims 1-27, wherein the antibody or immunoconjugate is administered at a dose of from about 100 mg / m2to about200 mg / m2as a loading dose, in particular of about 135 mg / m2, about 150 mg / m2or about 170 mg / m2, as a loading dose.