Therapeutic protein formulations comprising anti-DNABII antibodies and uses thereof
The present disclosure is directed to an aqueous therapeutic protein formulation including: (i) one or more therapeutic proteins, wherein the one or more therapeutic proteins include one or more anti-DNABII antibodies or antigen-binding fragments thereof in an amount ranging from 10 to 150 mg/mL; (ii) histidine buffer, (iii) NaCl, and (iv) an aqueous carrier, wherein a pH of the aqueous therapeutic formulation ranges from 5.5-8.0, and wherein the formulation is formulated for respiratory tract delivery and produces particles including the one or more therapeutic proteins upon aerosolization. Methods of generating an aerosol and treating biofilm-associated diseases or disorders, e.g., cystic fibrosis, ventilator-associated pneumonia, and acute exacerbations of chronic obstructive pulmonary disease or chronic bronchitis are also provided.
1 . A stable aqueous therapeutic protein formulation comprising:
(i) one or more therapeutic proteins, wherein the one or more therapeutic proteins comprise one or more anti-DNABII antibodies in an amount ranging from 10 to 150 mg/mL, wherein at least one anti-DNABII antibody is selected from the group consisting of
(a) the heavy and the light chain of a first antibody comprises: the TRL 1068 heavy chain CDR sequences HCDR1/HCDR2/HCDR3 (SEQ ID NO: 1) and the TRL 1068 light chain CDR sequences LCDR1/LCDR2/LCDR3 (SEQ ID NO: 4), and/or
(b) wherein the one or more anti-DNABII antibodies binds to the same epitope as the antibody of (a) and comprises a heavy and a light chain, wherein the heavy chain comprises: a polypeptide having at least 90% sequence identity with the TRL1068 heavy chain CDR sequences HCDR1/HCDR2/HCDR3 (SEQ ID NO: 1) and the light chain comprises a polypeptide having at least 90% identity with the TRL1068 light chain CDR sequences LCDR1/LCDR2/LCDR3 (SEQ ID NO: 4); and/or
(c) the heavy and the light chain of a second antibody comprises: the TRL1330 heavy chain CDR sequences HCDR1/HCDR2/HCDR3 (SEQ ID NO: 2) and the TRL1330 light chain CDR sequences LCDR1/LCDR2/LCDR3 (SEQ ID NO: 5);
(d) wherein the one or more anti-DNABII antibodies binds to the same epitope as the antibody of (c) and comprises a heavy and a light chain, wherein the heavy chain comprises: a polypeptide having at least 90% sequence identity with the TRL1330 heavy chain CDR sequences HCDR1/HCDR2/HCDR3 (SEQ ID NO: 2) and the light chain comprises a polypeptide having at least 90% identity with TRL1330 light chain CDR sequences LCDR1/LCDR2/LCDR3 (SEQ ID NO: 5)
(e) the heavy and the light chain of a third antibody comprise: the TRL1337 heavy chain CDR sequences, HCDR1/HCDR2/HCDR3 (SEQ ID NO: 3) and the TRL 1337 light chain CDR sequences (LCDR1/LCDR2/LCDR3 of SEQ ID NO: 6), and
(f) wherein the one or more anti-DNABII antibodies binds to the same epitope as the antibody of (e) and comprises a heavy and a light chain, wherein the heavy chain comprises: a polypeptide having at least 90% sequence identity with the TRL 1337 heavy chain CDR sequences, HCDR1/HCDR2/HCDR3 (SEQ ID NO: 3) and the light chain comprises a polypeptide having at least 90% identity with LCDR1/LCDR2/LCDR3 (SEQ ID NO: 6);
(ii) histidine buffer,
(iii) NaCl,
(iv) an aqueous carrier, and (v) a surfactant,
wherein a pH of the aqueous therapeutic formulation ranges from 5.5-8.0, and wherein the formulation is formulated for respiratory tract delivery and produces particles comprising the one or more therapeutic proteins upon aerosolization.
2 . The aqueous therapeutic protein formulation of claim 1 , wherein the histidine buffer comprises histidine chloride.
3 . The aqueous therapeutic protein formulation of claim 1 , wherein the concentration of the therapeutic protein ranges from 30 mg/mL to about 70 mg/mL.
4 . The aqueous therapeutic protein formulation of claim 1 , wherein the concentration of therapeutic protein is about 20 mg/mL.
5 . The aqueous therapeutic protein formulation of claim 1 , wherein the NaCl is at a concentration of about 115 mM.
6 . The aqueous therapeutic protein formulation of claim 1 , wherein the formulation further comprises a non-ionic surfactant.
7 . The aqueous therapeutic protein formulation of claim 6 , wherein the non-ionic surfactant comprises a polysorbate.
8 . The aqueous therapeutic protein formulation of claim 7 , wherein the polysorbate comprises polysorbate 20 in an amount of about 0.02%.
9 . The aqueous therapeutic protein formulation of claim 1 , wherein the pH of the aqueous formulation ranges from 6.0-6.5.
10 . The aqueous therapeutic protein formulation of claim 1 , wherein the pH of the formulation is about 6.0.
11 . The aqueous therapeutic protein formulation of claim 1 , wherein histidine is present in the formulation at a concentration of about 20 mM.
12 . The aqueous therapeutic protein formulation of claim 1 , wherein the one or more anti-DNABII antibodies comprises: a heavy and a light chain comprising, respectively (a1) the TRL1068 heavy chain CDR sequences HCDR1/HCDR2/HCDR3 (SEQ ID NO: 1) and the TRL1068 light chain CDR sequences LCDR1/LCDR2/LCDR3 (SEQ ID NO: 4);
(b1) the TRL 1330 heavy chain CDR sequences HCDR1/HCDR2/HCDR3 (SEQ ID NO: 2) and the TRL1330 light chain CDR sequences LCDR1/LCDR2/LCDR3 (SEQ ID NO: 5); and
(c1) the TRL 1337 heavy and the light chain CDR sequences, HCDR1/HCDR2/HCDR3 (SEQ ID NO: 3), and LCDR1/LCDR2/LCDR3 (SEQ ID NO: 6).
13 . The aqueous therapeutic protein formulation of claim 1 , wherein the one or more anti-DNABII antibodies comprises at least three anti-DNABII antibodies each of which comprises a heavy and light chain, wherein
(i) the heavy and the light chain of the first antibody comprises: the TRL1068 heavy chain CDR sequences HCDR1/HCDR2/HCDR3 (SEQ ID NO: 1) and the TRL1068 light chain CDR sequences LCDR1/LCDR2/LCDR3 (SEQ ID NO: 4);
(ii) the heavy and the light chain of the second antibody comprises: the TRL1330 heavy chain CDR sequences HCDR1/HCDR2/HCDR3 (SEQ ID NO: 2) and the TRL1330 light chain CDR sequences LCDR1/LCDR2/LCDR3 (SEQ ID NO: 5); and
(iii) the heavy and the light chain of the third antibody comprise: the TRL1337 heavy chain CDR sequences, HCDR1/HCDR2/HCDR3 (SEQ ID NO: 3) and the TRL1337 light chain CDR sequences (LCDR1/LCDR2/LCDR3 of SEQ ID NO: 6).
14 . The aqueous therapeutic protein formulation of claim 1 , wherein the one or more therapeutic proteins do not lose more than 15% of its biological activity during storage relative to an activity of the therapeutic protein at beginning of storage, wherein storage is at least for 3 month at 2° C.-8° C.
15 . The aqueous therapeutic protein formulation of claim 1 , wherein the storage is for a period in the range of three month to two years.
16 . The aqueous therapeutic formulation according to claim 1 , wherein the aqueous therapeutic formulation is a pharmaceutical aqueous therapeutic formulation.
17 . The aqueous therapeutic protein formulation of claim 1 , further comprising an antibiotic.
18 . The aqueous therapeutic protein formulation of claim 17 , wherein the antibiotic is an aminoglycoside or monobactam.
19 . The aqueous therapeutic protein formulation of claim 18 , wherein the aminoglycoside is tobramycin.
20 . The aqueous therapeutic protein formulation of claim 18 , wherein the monobactam is aztreonam.