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CN-122028938-A - Pharmaceutical combination comprising an anti-CD 37 antibody maytansinoid conjugate and a BCL2 inhibitor or PI3K inhibitor

CN122028938ACN 122028938 ACN122028938 ACN 122028938ACN-122028938-A

Abstract

The present invention relates to a pharmaceutical combination for the treatment of diseases. In particular, the present invention relates to a combination comprising a CD 37-targeting ligand-drug conjugate and an adjuvant selected from BCL2 inhibitors and PI3K pathway inhibitors, and its use in the treatment of cancer, in particular DLBCL.

Inventors

  • F Baer Toni
  • A. Arivas
  • S. Napoli

Assignees

  • 德彪药业国际股份公司

Dates

Publication Date
20260512
Application Date
20241018
Priority Date
20231018

Claims (15)

  1. 1. A conjugated compound comprising the formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, and a combination of an adjuvant selected from the group consisting of a BCL2 inhibitor or a pharmaceutically acceptable salt, solvate or polymorph thereof, and a PI3K pathway inhibitor or a pharmaceutically acceptable salt, solvate or polymorph thereof, wherein formula (I) is V(-LL-D) m (I) Wherein V represents an anti-CD 37 antibody, a fragment or derivative thereof, or an Fc-fusion protein comprising an anti-CD 37 antibody fragment, preferably natalizumab, a fragment or derivative thereof or an Fc-fusion protein comprising a fragment of natalizumab, LL represents a linker covalently bound to V and D, D represents a moiety derived from a drug selected from the group consisting of maytansine, maytansinoine (DM 1) and lamentacine (DM 4), preferably DM1 or DM4, more preferably DM1, and M is an integer from 1 to 12, preferably from 2 to 10, more preferably from 4 to 8.
  2. 2. The combination of claim 1, wherein the conjugated compound of formula (I) is a compound represented by one of the following formulas: Wherein, the D has the same meaning as defined in claim 1, preferably D is a moiety derived from DM1 or DM 4; x is a group of formula (IIIa), –(CH 2 ) n2 –(C=A)– ' (IIIa) Wherein n2 is 1 or 2, A is selected from O and S, preferably O; representing a covalent linkage to D, and ' Represents a covalent linkage to an adjacent amino acid Arg, cit or Phe, preferably a group of formula (IVc) or (IVd) Or (b) X is a group represented by formula (IVe) or (IVf) Represents a covalent linkage to D; ' means covalent linkage to an adjacent amino acid Arg, cit or Phe; Y is a group derived from a compound selected from the group consisting of maleimide, triazole, hydrazone, carbonyl-containing compounds and derivatives thereof, preferably selected from the group consisting of maleimide and derivatives thereof, such as ring-opening hydrolyzed maleimide derivatives, more preferably maleimide derived from ring-opening hydrolysis; T is derived from an amino acid selected from the group consisting of N- ε -propargyloxycarbonyl-L-lysine (Lys (Poc)), asp, glu, orn, lys, dab and Dap, preferably from Lys (Poc), glu, orn or Lys, more preferably from Lys; S is a moiety of formula (V) –X 1 –(CH 2 CH 2 O) n3 –X 2 (V) Wherein, the N3 is an integer from 6 to 200, preferably from 10 to 150, more preferably from 12 to 80, in particular from 1, or from 12 to 30, or from 14 to 25, or from 15 to 19; Represents a side chain covalently linked to T, preferably T; X 1 is selected from a single covalent bond, - (c=o) -and-N (R) -, wherein R represents a hydrogen atom, an alkyl group or a cycloalkyl group; X 2 represents an alkyl group having 1 to 6 carbon atoms, a carbonyl-containing group such as acetyl, OR a group of formula- (CH 2 ) n4 -CO 2 H), a sulfur-containing carbonyl group, a group of formula- (CH 2 ) n4 OR, a group of formula- (CH 2 ) n4 -SO 3 H), OR an amino-containing group such as- (CH 2 ) n4 -(C=A)-N(R) 2 OR- (CH 2 ) n4 -N(R) 2 ) wherein A is O OR S, each R is independently selected from hydrogen, alkyl and cycloalkyl, and n4 is an integer of 1 to 6; S' is a moiety represented by the formula θ1-(C=O) sn1 -(CH 2 -CH 2 -O) sn2 -(CH 2 ) sn3 -(NH) sn4 -θ2 Wherein sn1 and sn4 are independently selected from 0 and 1, sn2 is selected from 2 to 8, preferably 3 to 7, more preferably 4 to 6, and sn3 is selected from 1 and 2, wherein most preferably sn1 and sn4 are each 1, sn2 is 5, and sn3 is 2, and wherein θ1 is the position forming a covalent bond with the Lys side chain, and θ2 is the position forming a covalent bond with Y; Z is-OH, and N is 1.
  3. 3. The combination according to claim 2, wherein the group S in the conjugated compound of formula (I) is represented by the moiety of formula (V), wherein X 1 is- (c=o) -, X 2 is methyl, n3 is selected from 1 or from the range of 12 to 30, 14 to 25, 14 to 20, 15 to 19, and 16 to 18.
  4. 4. A combination according to any one of claims 2 and 3, wherein the group Y in the conjugated compound of formula (I) is represented by a divalent group represented by any one of the following formulas (XIIIa): formula (XIIIa) Wherein, the R 3 represents- (CH 2 ) n7 -(C=A) n9 - α '), or- (CH 2 ) n7 -(C=A) n9 -NH-(CH 2 CH 2 O) n8 -(C=A) n9 - α ', preferably- (CH 2 ) n7 -(C=A) n9 - α '), wherein, N7 is 1 or 2, preferably 1, N8 is a number from 1 to 6, preferably 1, N9 is 0 or 1, preferably 1, and A is O or S, preferably O; Wherein the methylene carbon atom of R 3 is covalently attached to the nitrogen atom of formula (XIIIa) and the carbonyl or thiocarbonyl carbon is covalently attached to T; Beta represents a covalent linkage with V, and Alpha' represents a covalent linkage to T, preferably through the formation of an amide bond with the amino group attached to C alpha of the amino acid.
  5. 5. The combination according to any one of claims 2, 3 and 4, wherein the conjugated compound of formula (I) is a compound of the following structure: Wherein D, X, Z, T, Y, S, V, n and m are as defined in any one of the preceding claims, preferably wherein D is a moiety derived from DM 1; X is a group represented by formula (IVc) (IVc) Represents a covalent linkage to D; ' means covalent linkage to an adjacent amino acid Cit; y is of formula (XIIIa) as defined in claim 4, wherein R 3 represents- (CH 2 ) n7 -(C=A) n9 -alpha'), in which, N7 is a number of times 1, N9 is 1, and A is O; wherein the methylene carbon atom of R 3 is covalently attached to the nitrogen atom of formula (XIIIa) and the carbonyl carbon is covalently attached to T to form an amide bond with Lys; Beta represents a covalent linkage with V, and Alpha' represents a covalent linkage to T, preferably by forming an amide bond with the amino group attached to C alpha of the amino acid, T is derived from an amino acid selected from Lys (Poc), glu, orn or Lys, preferably from Lys; s is as defined in claim 3; Z is-OH; v is derived from natalizumab, and N is 1.
  6. 6. The combination according to any one of claims 1 to 5, wherein the conjugated compound of formula (I) is represented by one of the following formulas: Wherein Y, V and m are as defined in any preceding claim, preferably wherein Y is as defined in claim 4, V is natalizumab, m is 2 to 10, With the proviso that V is understood to lie outside the brackets, so that m is not applicable to V, and with the proviso that the number of oxyethylene groups can be selected from the range of 12 to 30, preferably 14 to 25, more preferably 15 to 19.
  7. 7. The combination according to any one of claims 1 to 5, wherein the conjugated compound of formula (I) is represented by one of the following formulas: wherein V and m are as defined in any of the preceding claims, preferably V is natalizumab, m is 4 to 8, With the proviso that V is understood to lie outside the brackets, so that m is not applicable to V, and that the number of the precursor ethylene oxide groups can be selected from the range of 12 to 30, preferably 14 to 25, more preferably 15 to 19, Or a compound of formula (I) wherein V is as defined in claim 1 and preferably derived from natalizumab, and the-LL-D moiety is represented by the formula: 。
  8. 8. The combination according to claim 1, wherein the conjugated compound of formula (I) contains a linker LL selected from the group consisting of N-succinimidyl 4- (2-pyridyldithio) valerate (SPP), N-succinimidyl 4- (2-pyridyldithio) butyrate (SPDB) or N-succinimidyl 4- (2-pyridyldithio) -2-sulphobutyrate (sulfoo-SPDB), N-succinimidyl 4- (maleimidomethyl) cyclohexane carboxylate (SMCC), N-sulphosuccinimidyl 4- (maleimidomethyl) cyclohexane carboxylate (sulfoSMCC), N-succinimidyl-4- (iodoacetyl) -aminobenzoate (SIAB), and N-succinimidyl- [ (N-maleimidopropionamide) -tetraethyleneglycol ] ester (NHS-PEG 4-maleimide), preferably SMCC or NHS-PEG 4-maleimide.
  9. 9. The combination according to claim 1 or 8, wherein the conjugate compound of formula (I) is natalizumab maytansinoid (Debio 1562).
  10. 10. The combination according to any one of claims 1 to 9, wherein the combination comprises a BCL2 inhibitor selected from the group consisting of valnemulin (ABT-199), gossypol, sotopram (BGB 11417), nano-valnemulin (ABT-263), obagrura (GX 15-070), obagrura mesylate, ABT-737, AZD4320, AZD0466 (which is a conjugate of AZD4320 with PEG and polylysine dendrimer), TW-37, antimycin a, apogossypol one (Apo-G2), HA14-1 and chelerythrine, or a pharmaceutically acceptable salt, solvate or polymorph thereof.
  11. 11. The combination according to claim 10, wherein the BCL2 inhibitor is a BCL 2-selective inhibitor, preferably valnemulin.
  12. 12. The combination according to any one of claims 1 to 9, wherein the combination comprises AN inhibitor of the PI3K pathway or a pharmaceutically acceptable salt, solvate or polymorph thereof, and the PI3K pathway inhibitor is selected from PI3K inhibitors, the PI3K inhibitor may for example be selected from IPI-145, idarubicin (CAL-101), bupirimate (AN 2025), luo Geli xib (MSC 2360844), copanide (BAY 80-6946), IC-87114, PIK-93, pitirimate (GDC-0941), dacrile (BEZ 235), GSK1059615, BX-912, SF1126, pinallide (SAR 245408), watalide (SAR 245409), BGT226, ji Dali plug (PKI-587), NVPBE235, lazoyside (CH 5132799), zstk474, sonoliib (PX-866), B591, TG 100-115) RIDR-PI-103, april (BYL 719), sela Bei Lixi (INK-117), GSK2636771, zanril (ME-401), AMG319, lin Puli plug (YY-20394), paspalide (INCB 050465), wu Pali (TGR-1202), PF-04691502, tenalide (RP 6530), taceririnotecan (GDC-0032), AZD8186, AZD8835, develilplug (IPI-145), leno Li Xibu (CDZ 173), igalilex (IPI-549), apitolibu (GDC-0980), or Mi Lisai (GSK 2126458), sha Motuo lixib (3023414), ratio Mi Lisai (PQR 309), pa Sha Lixi cloth (GDC-0084), wostarism (XL 765), SAR245409, VS-5584; Akt inhibitors which may be selected, for example, from AT7867, MK-2206, pirifacin (KRX-0401), troxiribine, patadine (RG 7440), arfipronil (GSK 2110183), niprotil (GSK 2141795), carboplatin (AZD 5363), solenopoxin analogues, HY-10249A, AT13148, KP372-1, GSK690693, E Lu Fuxin, phosphorylcholine erulate, rimofoxine, edestin, or An mTOR inhibitor may be selected, for example, from everolimus (everolismus), temsirolimus (temsirolismus), KU 0063794, AZD 8055, li Luomo span (ridaforolismus, AP 23573), ulmoschus (umirolismus), zotarolimus (zotarolismus), tolin 1, sapachlor (sapanisertib, INK 128), valvular (AZD 2014), PP242, OSI-027, WYE354, WYR-125132, INK128/MLN-0128, ground phosphorus span (deforolismus), oncorubicin (onatasertib, CC-223), and PI3K/mTOR dual inhibitors, such as dactylosin, pi Lali span (pilarlisib), wostarils, apitolibu, ji Dali plug, BGT226, GSK2126458, PF-04691502, VS-5584, SF-1126, and Preferably, the Idalteparis, IPI-145, IC-87114, PIK-93, GDC-0941, GSK1059615, KU0063794, AZD8055, MK-2206 or troxiribine.
  13. 13. A combination according to any one of the preceding claims for use in the treatment of cancer.
  14. 14. The combination of claim 13, wherein the cancer is DLBCL.
  15. 15. A conjugated compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof for use in a method of treating cancer, wherein the cancer is preferably DLBCL, wherein the method comprises administering the conjugated compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof in combination with an adjuvant selected from a BCL2 inhibitor or a pharmaceutically acceptable salt, solvate or polymorph thereof and a PI3K pathway inhibitor or a pharmaceutically acceptable salt, solvate or polymorph thereof, Wherein the conjugated compound of formula (I) is as defined in any one of claims 1 to 9, and wherein the BCL2 inhibitor or a pharmaceutically acceptable salt, solvate or polymorph thereof and the PI3K pathway inhibitor or a pharmaceutically acceptable salt, solvate or polymorph thereof are preferably as defined in any one of claims 10 to 12.

Description

Pharmaceutical combination comprising an anti-CD 37 antibody maytansinoid conjugate and a BCL2 inhibitor or PI3K inhibitor Technical Field The present invention relates to a pharmaceutical combination for the treatment of diseases. In particular, the present invention relates to the combination of ligand-drug conjugates with BCL2 inhibitors or PI3K pathway inhibitors and their use in the treatment of cancer, in particular in the treatment of diffuse large B-cell lymphoma (DLBCL). Background A variety of therapeutic approaches for treating cancer are currently known, including antibody drug conjugates, such as the commercial product Kadcyla based on trastuzumab (trastuzumab). However, there is an urgent need for further effective cancer therapies. Disclosure of Invention The present invention provides novel pharmaceutical combinations. The combination is suitable for cancer therapy, in particular for the treatment of DLBCL. Accordingly, the present invention provides the following: 1. A conjugated compound comprising the formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, and a combination of an adjuvant selected from the group consisting of a BCL2 inhibitor or a pharmaceutically acceptable salt, solvate or polymorph thereof, and a PI3K pathway inhibitor or a pharmaceutically acceptable salt, solvate or polymorph thereof, wherein formula (I) is V(-LL-D)m (I) Wherein V represents an anti-CD 37 antibody, a fragment or derivative thereof, or an Fc-fusion protein comprising an anti-CD 37 antibody fragment, preferably natalizumab, a fragment or derivative thereof or an Fc-fusion protein comprising a fragment of natalizumab, LL represents a linker covalently bound to V and D, D represents a moiety derived from a drug selected from the group consisting of maytansine (maytansine), maytansinoine (DM 1) and lamivudine (DM 4), preferably DM1 or DM4, more preferably DM1, and M is an integer from 1 to 12, preferably from 2 to 10, more preferably from 4 to 8. 2. The combination of clause 1, wherein the conjugated compound of formula (I) is a compound represented by one of the following formulas: Wherein, the D has the same meaning as defined in claim 1, preferably D is a moiety derived from DM1 or DM 4; x is a group of formula (IIIa), -(CH2)n2-(C=A)-' (IIIa) Wherein n2 is 1 or 2, A is selected from O and S, preferably O; representing a covalent linkage to D, and ' Represents a covalent linkage to an adjacent amino acid Arg, cit or Phe, preferably a group of formula (IVc) or (IVd) Or (b) X is a group represented by formula (IVe) or (IVf) Represents a covalent linkage to D; ' means covalent linkage to an adjacent amino acid Arg, cit or Phe; Y is a group derived from a compound selected from the group consisting of maleimide, triazole, hydrazone, carbonyl-containing compounds and derivatives thereof, preferably selected from the group consisting of maleimide and derivatives thereof, such as ring-opening hydrolyzed maleimide derivatives, more preferably maleimide derived from ring-opening hydrolysis; T is derived from an amino acid selected from the group consisting of N- ε -propargyloxycarbonyl-L-lysine (Lys (Poc)), asp, glu, orn, lys, dab and Dap, preferably from Lys (Poc), glu, orn or Lys, more preferably from Lys; S is a moiety of formula (V) -X1-(CH2CH2O)n3-X2 (V) Wherein, the N3 is an integer from 6 to 200, preferably from 10 to 150, more preferably from 12 to 80; Represents a side chain covalently linked to T, preferably T; X 1 is selected from a single covalent bond, - (c=o) -and-N (R) -, wherein R represents a hydrogen atom, an alkyl group or a cycloalkyl group; X 2 represents an alkyl group having 1 to 6 carbon atoms, a carbonyl-containing group such as acetyl, OR a group of formula- (CH 2)n4-CO2 H), a sulfur-containing carbonyl group, a group of formula- (CH 2)n4 OR, a group of formula- (CH 2)n4-SO3 H), OR an amino-containing group such as- (CH 2)n4-(C=A)-N(R)2 OR- (CH 2)n4-N(R)2) wherein A is O OR S, each R is independently selected from hydrogen, alkyl and cycloalkyl, and n4 is an integer of 1 to 6; S' is a moiety represented by the formula θ1-(C=O)sn1-(CH2-CH2-O)sn2-(CH2)sn3-(NH)sn4-θ2 Wherein sn1 and sn4 are independently selected from 0 and 1, sn2 is selected from 2 to 8, preferably 3 to 7, more preferably 4 to 6, and sn3 is selected from 1 and 2, wherein most preferably sn1 and sn4 are each 1, sn2 is 5, and sn3 is 2, and wherein θ1 is the position forming a covalent bond with the Lys side chain, θ2 is the position forming a covalent bond with Y; Z is-OH, and N is 1. 3. A combination according to item 2, wherein the group S in the conjugated compound of formula (I) is represented by the moiety of formula (V), wherein X 1 is- (c=o) -, X 2 is methyl, and n3 is selected from the range of 14 to 20, preferably 16 to 18. 4. A combination according to any one of items 2 and 3, wherein the group Y in the conjugated compound of formula (I) is represented by a divalent group represented by a