Method for preventing or treating nosocomial pneumonia

Abstract

A method for preventing or treating nosocomial diseases, e.g., diseases caused by Pseudomonas aeruginosa , is provided. The method includes administering to a susceptible human a specified dose of a bispecific antibody that that specifically binds Pseudomonas aeruginosa Psl and PcrV.

1 . A method of preventing or treating a  Pseudomonas aeruginosa  infection in a susceptible human subject comprising administering to the subject about 500 to about 3000 mg of a bispecific antibody that specifically binds  Pseudomonas aeruginosa  Psl and PcrV and monitoring the subject for symptoms for 21 days from the day of administration; wherein at 21 days post-administration the subject remains symptom-free or displays less severe symptoms relative to a cohort of susceptible human subjects administered a placebo;
 wherein the bispecific antibody comprises a binding domain which specifically binds to  P. aeruginosa  Psl comprising a set of complementarity determining regions (CDRs): HCDR1-Psl, HCDR2-Psl, HCDR3-Psl, LCDR1-Psl, LCDR2-Psl, and LCDR3-Psl, wherein HCDR1-Psl has the amino acid sequence of SEQ ID NO: 10, HCDR2-Psl has the amino acid sequence of SEQ ID NO: 11, HCDR3-Psl has the amino acid sequence of SEQ ID NO: 12, LCDR1-Psl has the amino acid sequence of SEQ ID NO: 13, LCDR2-Psl has the amino acid sequence of SEQ ID NO: 14, and LCDR3-Psl has the amino acid sequence of SEQ ID NO: 15; and a binding domain which specifically binds to  P. aeruginosa  PcrV comprising a set of CDRs: HCDR1-PcrV, HCDR2-PcrV, HCDR3-PcrV, LCDR1-PcrV, LCDR2-PcrV, and LCDR3-PcrV, wherein HCDR1-PcrV has the amino acid sequence of SEQ ID NO: 2, HCDR2-PcrV has the amino acid sequence of SEQ ID NO: 3, HCDR3-PcrV has the amino acid sequence of SEQ ID NO: 4, LCDR1-PcrV has the amino acid sequence of SEQ ID NO: 6, LCDR2-PcrV has the amino acid sequence of SEQ ID NO: 7, and LCDR3-PcrV has the amino acid sequence of SEQ ID NO: 8.   
     
     
         2 . The method of  claim 1 , wherein the infection is pneumonia, bacteremia, bone infection, joint infection, skin infection, burn infection, wound infection, or any combination thereof. 
     
     
         3 . The method of  claim 1 , wherein the infection is a nosocomial infection. 
     
     
         4 - 5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the bispecific antibody comprises a heavy chain constant region domain-1 (CH1) comprising the amino acid sequence of SEQ ID NO: 16. 
     
     
         7 . The method of  claim 1 , wherein the bispecific antibody comprises a first linker (L1) and a second linker (L2), wherein L1 and L2 are the same or different, and independently comprise (a) [GGGGS]n, wherein n is 0, 1, 2, 3, 4, or 5 (SEQ ID NO: 23), (b) [GGGG]n, wherein n is 0, 1, 2, 3, 4, or 5 (SEQ ID NO: 24), or a combination of (a) and (b). 
     
     
         8 . The method of  claim 1 , wherein the bispecific antibody comprises a first heavy chain hinge region fragment (H1) comprising the amino acid sequence EPKSC (SEQ ID NO: 17). 
     
     
         9 . The method of  claim 1 , wherein the bispecific antibody comprises a second heavy chain hinge region fragment (H2) comprising the amino acid sequence DKTHTCPPCP (SEQ ID NO: 18). 
     
     
         10 . The method of  claim 1 , wherein the bispecific antibody comprises a heavy chain constant region domain-2 (CH2) and a heavy chain constant region domain-3 (CH3), wherein the CH2-CH3 comprises the amino acid sequence of SEQ ID NO: 19. 
     
     
         11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 21, and the light chain comprises the amino acid sequence of SEQ ID NO: 22. 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 1 , wherein at the time of the administration the subject is colonized with  Pseudomonas aeruginosa  in the respiratory tract. 
     
     
         15 - 16 . (canceled) 
     
     
         17 . The method of  claim 14 , wherein the subject's respiratory tract is colonized with  P. aeruginosa  one, two, three, or four days prior to administration of the bispecific antibody. 
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 14 , wherein the subject's respiratory tract is additionally colonized by  Staphylococcus aureus  at the time of administration of the bispecific antibody. 
     
     
         20 . The method of  claim 1 , wherein the subject is about to be hospitalized, is currently hospitalized, was recently hospitalized, is on a mechanical ventilator, or a combination thereof. 
     
     
         21 . (canceled) 
     
     
         22 . The method of  claim 1 , wherein the subject is hospitalized in an intensive care unit (ICU) and is intubated. 
     
     
         23 . The method of  claim 20 , wherein the subject is mechanically ventilated through an endotracheal or nasotracheal tube. 
     
     
         24 . The method of  claim 20 , wherein the administration reduces the risk of pneumonia while on mechanical ventilation. 
     
     
         25 . (canceled) 
     
     
         26 . The method of  claim 1 , wherein 1500 mg of the bispecific antibody is administered. 
     
     
         27 . The method of  claim 1 , wherein 3000 mg of the bispecific antibody is administered. 
     
     
         28 . The method of  claim 14 , wherein the subject has not received antibiotics active against the  P. aeruginosa  strain with which the subject is colonized prior to administration of the bispecific antibody. 
     
     
         29 - 32 . (canceled) 
     
     
         33 . The method of  claim 1 , wherein the subject maintains a serum concentration of the bispecific antibody of at least about 1 μg/ml through day 21 following administration of the bispecific antibody. 
     
     
         34 - 35 . (canceled)