Dosage regime

Abstract

The present disclosure relates to the treatment of pathological conditions, such as cancer, with Antibody Drug Conjugates (ADCs). In particular, the present disclosure relates to administration of ADCs which bind to CD19 (CD19-ADCs).

1 - 99 . (canceled) 
     
     
         100 . A method of treating a proliferative disease in a subject, said method comprising administering to a subject (i) a CD19-antibody drug conjugate (ADC), wherein the CD19-ADC comprises as the drug, a pyrrolobenzodiazepine (P3D) dimer, linked to an antibody that binds to CD19 (Ab), the CD19-ADC having a drug to antibody ratio (DAR) of between 1 and 8; and (ii) Rituxinab,
 wherein (i) the CD19-ADC is administered to the subject in a tapered dosage regime comprising multiple treatment cycles.   
     
     
         101 . The method of  claim 100 , wherein the PBD dimer is of formula I: 
       
         
           
           
               
               
           
         
         wherein
 (a) R L1′  is a linker for connection to Ab; 
 (b) (i) R 20  and R 21  either together form a double bond between the nitrogen and carbon atoms to which they are bound; or (ii) R 20  is a capping group R C , and R 21  is OH; 
 (c) m is 0 or 1; and 
 (d) when there is a double bond between C2 and C3, R 2  is methyl; 
 
         when there is a single bond between C2 and C3, R 2  is either H or 
       
       
         
           
           
               
               
           
         
         when there is a double bond between C2′ and C3′, R 12  is methyl; 
         when there is a single bond between C2′ and C3′, R 2  is H or 
       
       
         
           
           
               
               
           
         
       
     
     
         102 . The method of  claim 100 , wherein Ab comprises a VH domain having the amino acid sequence of SEQ ID NO.2 and a VL domain having the amino acid sequence of SEQ ID NO. 8. 
     
     
         103 . The method of  claim 101 , wherein the PBD is: 
       
         
           
           
               
               
           
         
       
       wherein R L1′  is a linker for connection to Ab. 
     
     
         104 . The method of  claim 103 , wherein the CD19-ADC has the following structure: 
       
         
           
           
               
               
           
         
       
       wherein Ab comprises a VH domain having the amino acid sequence of SEQ ID NO.2 and a VL domain having the amino acid sequence of SEQ ID NO. 8. 
     
     
         105 . The method of  claim 100 , wherein the dose of CD19-ADC is reduced following the first or second treatment cycle. 
     
     
         106 . The method of  claim 100 , wherein the starting dose of CD19-ADC is reduced no more than once during the dosage regime. 
     
     
         107 . The method of  claim 100 , wherein the starting dose of CD19-ADC is from about 121 μg/kg to about 180 μg/kg. 
     
     
         108 . The method of  claim 107 , wherein the starting dose of CD19-ADC is from about 140 μg/kg to about 160 μg/kg. 
     
     
         109 . The method of  claim 100 , wherein each treatment cycle is about 3 weeks. 
     
     
         110 . The method of  claim 100 , wherein the dose of CD19-ADC is reduced following the second treatment cycle. 
     
     
         111 . The method of  claim 100 , wherein the dose of CD19-ADC is reduced by about 50%. 
     
     
         112 . The method of  claim 108 , wherein the dose of CD19-ADC is reduced by about 50%. 
     
     
         113 . The method of  claim 100 , wherein the dose of Rituximab is administered is about 325 to about 425 mg/m 2 . 
     
     
         114 . The method of  claim 113 , wherein the dose of Rituximab is administered is about 375 mg/m 2 . 
     
     
         115 . The method of  claim 113 , wherein the dose of Rituximab is administered in a Q3W dosage regime. 
     
     
         116 . The method of  claim 100 , wherein the subject has, or is suspected as having, or has been identified as being at risk of, or has received a diagnosis of cancer of a non-Hodgkin's Lymphoma, such as diffuse large B-cell lymphoma (DLBCL).