Extracellular targeted drug conjugates

Abstract

Extracellular drug conjugates (EDCs) targeting CD38 are useful in the treatment of diseases such as cancer and immune disorders, including asthma.

1 .- 14 . (canceled) 
     
     
         15 . A method for treating a disease comprising administering to a subject in need of treatment for said disease a therapeutically effective amount of an extracellular-targeted drug conjugate (EDC) comprising a targeting moiety linked by a stable or non-cleavable linker to an agent, wherein the targeting moiety binds to CD38, wherein the agent binds to or modifies the activity of a Na,K-ATPase, wherein the disease is optionally an immune disease such as asthma. 
     
     
         16 . A method for treating a disease comprising administering to a subject in need of treatment for said disease a therapeutically effective amount of an extracellular-targeted drug conjugate (EDC) of Formula (I):
   [TARGETING MOIETY]-[LINKER]-[AGENT]  Formula (I)
   
       wherein:
 [Targeting Moiety] is an antibody that binds to CD38; 
 [Agent] is a cardiotonic steroid or a cardenolide; and 
 [Linker] has a formula of Formula (II): 
 
       
         
           
           
               
               
           
         
         wherein: X 1  is optionally present and when present is 
       
       
         
           
           
               
               
           
         
       
       and d is 0 to 6;
 X 2 , X 3  and X 4  are each optionally present and when present are individually selected from alkyl, ketone, —C(O)NH—, —C(O)NR 8 —, —O—, —S—, —NH—, —NR 9 —, wherein R 8  and R 9  are individually selected from alkyl (e.g., methyl), heteroalkyl, aryl, and heteroaryl; 
 X 5  and X 6  are each individually selected from CR 10  and N, wherein R 10  is H, branched alkyl, unbranched alkyl, saturated alkyl, or unsaturated alkyl; 
 X 7  is optionally present and when present is selected from —C(O)—, —OC(O)—, —NHC(O)—, —NR 11 C(O)—, wherein R 11  is H, branched alkyl, unbranched alkyl, saturated alkyl, or unsaturated alkyl; 
 R 1  is optionally present and when present is selected from branched alkyl, unbranched alkyl, saturated alkyl, or unsaturated alkyl; 
 each of R 2 , R 3  and R 6  is optionally be present and when present each is individually selected from branched alkyl, unbranched alkyl, saturated alkyl, and unsaturated alkyl; 
 each of R 4  and R 5  is optionally present and when present is individually selected from branched alkyl, unbranched alkyl, saturated alkyl, or unsaturated alkyl, with the proviso that at least one of R 4  and R 5  must be present; 
 a is 0 to 99; 
 b is 0 to 99; and 
 c is 0 to 99, wherein the disease is optionally an immune disease such as asthma. 
 
     
     
         17 . The method of  claim 15 , wherein the targeting moiety includes an antibody targeting moiety that binds a CD38 epitope selected from the group consisting of SUN4B7, HB7, OKT10, D34, AT1, SAR650984, 38SB19, daratumumab, MOR202 antibodies and any binding fragment thereof. 
     
     
         18 . The method of  claim 15 , wherein the targeting moiety is a SUN4B7 antibody or binding fragment thereof, or an antibody or binding fragment thereof that binds to the same or substantially similar CD38 epitope as SUNB47. 
     
     
         19 . The method of  claim 15 , wherein the targeting moiety is an AT1 antibody or binding fragment thereof, or an antibody or binding fragment thereof that binds to the same or substantially similar CD38 epitope as AT1. 
     
     
         20 . The method of  claim 15 , wherein the linker includes at least one nitrogen heteroatom. 
     
     
         21 . The method of  claim 20 , wherein the at least one nitrogen atom is a tertiary nitrogen atom. 
     
     
         22 . The method of  claim 15 , wherein the linker comprises at least one ethylene glycol moiety. 
     
     
         23 . The method of  claim 22 , wherein the polyethylene glycol is PEG24 or PEG36. 
     
     
         24 . The method of  claim 15 , wherein the agent is a cardenolide or cardiotonic steroid. 
     
     
         25 . The method of  claim 24 , wherein the cardiotonic steroid is bufalin, digitoxigenin, scillarenin, or a derivative of any of the foregoing.