Dosage of claudin-6 conjugates for cancer treatment
View Patent ↗Described herein are methods for inhibiting a solid tumor expressing claudin-6 in a human subject, comprising administering to the human subject an effective amount of a composition comprising conjugates of a CLDN6-specific antigen-binding protein covalently bound to heterologous moieties comprising structural formula (I): wherein a first plurality of the conjugates are bound to four heterologous moieties comprising structural formula (I); at least about 95% of the first plurality of conjugates are structurally homogenous; and the effective amount is in a range of about 1.0 mg of conjugate/kg weight of the subject to 10 mg of conjugate/kg weight of the subject.
1. A method for inhibiting a solid tumor expressing claudin-6 (CLDN6) in a human subject, comprising administering to the human subject an effective amount of a composition comprising conjugates of a CLDN6-specific antigen-binding protein covalently bound to heterologous moieties of structural formula (II):
wherein
is a bond and a sulfur atom of the CLDN6-specific antigen-binding protein;
the CLDN6-specific antigen-binding protein comprises an antibody that binds CLDN6 or antigen-binding fragment thereof comprising:
(i) HC CDR1 having a sequence GFTFSNYW (SEQ ID NO: 23);
(ii) HC CDR2 having a sequence IRLKSDNYAT (SEQ ID NO: 24),
(iii) HC CDR3 having a sequence NDGPPSGS (SEQ ID NO: 457),
(iv) LC CDR1 having a sequence ENIYSY (SEQ ID NO: 20),
(v) LC CDR2 having a sequence NAK, and
(vi) LC CDR3 having a sequence QHHYTVPWT (SEQ ID NO: 22);
a first plurality of the conjugates are bound to four heterologous moieties of structural formula (II);
at least about 95% of the first plurality of conjugates are structurally homogenous;
the average number of heterologous moieties per CLDN6-specific antigen-binding protein in the composition is about 3.5 to about 4;
the effective amount is in a range of about 2.4 mg/kg to 4.0 mg/kg; and
a dose normalized C max value for unbound circulating monomethyl auristatin E (MMAE) is less than about 35 μg/mL per mg of the conjugate after administration of the composition, thereby minimizing toxicity in the subject and inhibiting the solid tumor.
2. The method of claim 1 , wherein the dose normalized C max value for unbound circulating MMAE is less than about 30 pg/mL per mg.
3. The method of claim 2 , wherein the dose normalized C max value for unbound circulating MMAE is less than about 25 pg/mL per mg.
4. The method of claim 3 , wherein the dose normalized C max value for unbound circulating MMAE is less than about 20 μg/mL per mg.
5. The method of claim 4 , wherein the dose normalized C max value for unbound circulating MMAE is less than about 15 μg/mL per mg.
6. The method of claim 5 , wherein the dose normalized C max value for unbound circulating MMAE is less than about 10 μg/mL per mg.
7. The method of claim 1 , wherein the effective amount is about 3 mg/kg.
8. The method of claim 1 , wherein the effective amount is about 3.6 mg/kg.
9. The method of claim 1 , wherein the effective amount is about 4 mg/kg.
10. The method of claim 1 , wherein the solid tumor is an ovarian tumor.
11. The method of claim 1 , wherein the solid tumor is a bladder tumor.
12. The method of claim 1 , wherein the solid tumor is a testicular tumor.
13. The method of claim 1 , wherein the solid tumor is an endometrial tumor.
14. The method of claim 1 , wherein the effective amount is in the range of about 2.4 mg/kg to 3.0 mg/kg.
15. The method of claim 1 , wherein the effective amount is in the range of about 3 mg/kg to about 3.6 mg/kg.
16. The method of claim 1 , wherein the composition is administered intravenously.
17. The method of claim 1 , wherein the average number of heterologous moieties per CLDN6-specific antigen-binding protein in the composition is about 3.6 to about 3.9, or about 3.7 to about 3.8.
18. The method of claim 1 , wherein, in the first plurality of conjugates, the heterologous moieties are covalently conjugated at unpaired cysteine residues of the CLDN6-specific antigen-binding protein.
19. The method of claim 1 , wherein, in the first plurality of conjugates, the heterologous moieties are covalently conjugated at cysteine residues resulting from cleavage of the heavy chain-light chain interchain disulfide bonds of the CLDN6-specific antigen-binding protein.
20. The method of claim 1 , wherein about 95%, about 96%, about 97%, or about 98% of the first plurality of conjugates are structurally homogenous.
21. The method of claim 1 , wherein at a C max after administration, percent of unbound circulating MMAE in serum is less than about 0.007% C max of total CLDN6-specific antigen-binding proteins.
22. The method of claim 1 , wherein at a C max after administration, percent of unbound circulating MMAE in serum is less than about 0.005% C max of total CLDN6-specific antigen-binding proteins.
23. The method of claim 1 , wherein at a C max after administration, percent of unbound circulating MMAE in serum is less than about 0.018% C max of the conjugate.
24. The method of claim 1 , wherein at a C max after administration, percent of unbound circulating MMAE in serum is less than about 0.01% C max of the conjugate.
25. The method of claim 1 , wherein at a C max after administration, percent of unbound circulating MMAE in serum is less than about 0.007% C max of the conjugate.
26. The method of claim 1 , wherein the effective amount of the composition is administered once every 1-4 weeks, once every 2-4 weeks, or once every 3 weeks.
27. The method of any one of the preceding claims , wherein the method further comprises, prior to administration of the composition, administering a granulocyte-colony stimulating factor (G- CSF) to the subject.