IP Library › Granted Patent US 10,377,813

Granted Patent B2

US 10,377,813 · App. 15/422,827 · Granted Aug 13, 2019

Peptide-mediated non-covalent delivery of active agents across the blood-brain barrier

Inventors: Geoffry L. Curran (Rochester, MN); Gobinda Sarkar (Rochester, MN); Joseph F. Poduslo (Zumbro Falls, MN); Robert B. Jenkins (Rochester, MN); Val J. Lowe (Rochester, MN); Eric W. Mahlum (Rochester, MN)

Assignee: Mayo Foundation for Medical Education and Research

C07K14/775 A61K38/47 A61K39/39533 A61K47/64 A61K49/0056 A61K49/0058 A61K51/088 A61K51/1018 A61K51/12 C12Y302/01023

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Quick Facts

Patent No.: US 10,377,813
App. No.: 15/422,827
Granted: Aug 13, 2019
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

The peptides described herein can function as carrier peptides. These peptides can associate with (e.g., non-covalently bind) biologically active molecules or imaging agents to transport the biologically active molecules or imaging across the blood-brain barrier. In some cases, such transport may increase the effectiveness of the biological molecules or imaging agents.

Claims (323)

1. A method of transporting a biologically active molecule or imaging agent across the blood-brain barrier of a subject, the method comprising administering to the subject a complex, or a pharmaceutically acceptable salt thereof, comprising the biologically active molecule or imaging agent associated with a carrier peptide; wherein the carrier peptide consists of the sequence:

X n —[B] m

or a pharmaceutically acceptable salt thereof, wherein:

X is a hydrophilic amino acid;

B is a blood-brain barrier agent of the sequence

(SEQ ID NO: 29)

L-R-X1-R-X2-X3-X4-H-L-R-X5-X6-X7-K-R-L-X8-R-D-X9,

wherein:

X1 is selected from the group consisting of A, L, S, and V;

X2 is selected from the group consisting of L and M;

X3 is selected from the group consisting of A and S;

X4 is selected from the group consisting of N, S, and T;

X5 is selected from the group consisting of K and N;

X6 is selected from the group consisting of L, M, and V;

X7 is selected from the group consisting of R and P;

X8 is selected from the group consisting of L and M; and

X9 is selected from the group consisting of A and L;

n is an integer from 4 to 50; and

m is integer from 1 to 3.

2. The method of claim 1 , wherein each X is independently chosen from arginine, asparagine, aspartic acid, glutamic acid, glutamine, lysine, serine, threonine, and tyrosine.

3. The method of claim 2 , wherein n is chosen from 4, 8, 12, 16, and 20.

4. The method of claim 3 , wherein n is 16.

5. The method of claim 1 , wherein m is 1.

6. The method of claim 1 , wherein the imaging agent is chosen from 125 I-IgG and magnevist.

7. The method of claim 1 , wherein the biologically active molecule is chosen from a polypeptide, antibody, antibody fragment, antigen, and antigenic peptide.

8. The method of claim 7 , wherein the biologically active molecule is a polypeptide.

9. The method of claim 8 , wherein the polypeptide is a functional domain of a biologically active molecule chosen from growth factors, enzymes, and transcription factors.

10. The method of claim 8 , wherein the polypeptide is chosen from a brain derived neurotrophic factor, a fibroblast growth factor, a nerve growth factor, a neurotrophin, a glial derived neurotrophic factor, a ciliary neurotrophic factor, a neurturin, a neuregulin, an interleukin, a transforming growth factor, a vasoactive intestinal peptide, an epidermal growth factor, an erythropoietin, a growth factor a platelet derived growth factor, artemin, persephin, netrins, cardiotrophin-1, a stem cell factor, midkine, pleiotrophin, a bone morphogenic protein, a saposin, a semaporin, and a leukemia inhibitory factor.

11. The method of claim 7 , wherein the biologically active molecule is an antibody or antibody fragment chosen from anti-Aβ, anti-HER2, anti-EGF, anti-nogo A, antiTRAIL, anti-α-synuclein, anti-htt, anti-prion, and anti-West Nile virus.

12. The method of claim 1 , wherein the biologically active molecule or imaging agent is non-covalently bound to the carrier peptide.

13. The method of claim 1 , wherein the carrier peptide consists of the sequence:

(SEQ ID NO: 143)

[X] n -L-R-X1-R-X2-X3-X4-H-L-R-X5-X6-X7-K-R-L-X8-R-

D-X9

wherein:

X is lysine.

14. The method of claim 13 , wherein the carrier peptide consists of one of the sequences selected from the group consisting of:

(SEQ ID NO: 19)

K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 20)

K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-

R-D-A;

(SEQ ID NO: 21)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-

K-R-L-L-R-D-A;

(SEQ ID NO: 22)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-

R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 23)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-

A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 46)

K-K-K-K-L-R-S-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 47)

K-K-K-K-K-K-K-K-L-R-S-R-L-A-S-H-L-R-K-L-R-K-R-L-L-

R-D-A;

(SEQ ID NO: 48)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-S-R-L-A-S-H-L-R-K-L-R-

K-R-L-L-R-D-A;

(SEQ ID NO: 49)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-S-R-L-A-S-H-L-

R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 50)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-S-R-L-

A-S-H-L-R-K-L-R-K-R-L-L-R-D-;

(SEQ ID NO: 51)

K-K-K-K-L-R-V-R-M-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 52)

K-K-K-K-K-K-K-K-L-R-V-R-M-A-S-H-L-R-K-L-R-K-R-L-L-

R-D-A;

(SEQ ID NO: 53)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-M-A-S-H-L-R-K-L-R-

K-R-L-L-R-D-A;

(SEQ ID NO: 54)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-M-A-S-H-L-

R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 55)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-M-

A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 56)

K-K-K-K-L-R-V-R-L-A-T-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 57)

K-K-K-K-K-K-K-K-L-R-V-R-L-A-T-H-L-R-K-L-R-K-R-L-L-

R-D-A;

(SEQ ID NO: 58)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-T-H-L-R-K-L-R-

K-R-L-L-R-D-A;

(SEQ ID NO: 59)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-T-H-L-

R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 60)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-

A-T-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 61)

K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-P-K-R-L-L-R-D-A;

(SEQ ID NO: 62)

K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-P-K-R-L-L-

R-D-A;

(SEQ ID NO: 63)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-P-

K-R-L-L-R-D-A;

(SEQ ID NO: 64)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-

R-K-L-P-K-R-L-L-R-D-A;

(SEQ ID NO: 65)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-

A-S-H-L-R-K-L-P-K-R-L-L-R-D-A;

(SEQ ID NO: 66)

K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-M-R-D-A;

(SEQ ID NO: 67)

K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-M-

R-D-A;

(SEQ ID NO: 68)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-

K-R-L-M-R-D-A;

(SEQ ID NO: 69)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-

R-K-L-R-K-R-L-M-R-D-A;

(SEQ ID NO: 70)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-

A-S-H-L-R-K-L-R-K-R-L-M-R-D-A;

(SEQ ID NO: 71)

K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 72)

K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-L-R-K-R-L-L-

R-D-A;

(SEQ ID NO: 73)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-L-R-

K-R-L-L-R-D-A;

(SEQ ID NO: 74)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-

R-N-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 75)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-

A-S-H-L-R-N-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 76)

K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-V-R-K-R-L-L-R-D-A;

(SEQ ID NO: 77)

K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-V-R-K-R-L-L-

R-D-A;

(SEQ ID NO: 78)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-V-R-

K-R-L-L-R-D-A;

(SEQ ID NO: 79)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-

R-K-V-R-K-R-L-L-R-D-A;

(SEQ ID NO: 80)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-

A-S-H-L-R-K-V-R-K-R-L-L-R-D-A;

(SEQ ID NO: 81)

K-K-K-K-L-R-V-R-M-S-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 82)

K-K-K-K-K-K-K-K-L-R-V-R-M-S-S-H-L-R-K-L-R-K-R-L-L-

R-D-A;

(SEQ ID NO: 83)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-M-S-S-H-L-R-K-L-R-

K-R-L-L-R-D-A;

(SEQ ID NO: 84)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-M-S-S-H-L-

R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 85)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-M-

S-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 86)

K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-V-R-K-R-L-L-R-D-A;

(SEQ ID NO: 87)

K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-V-R-K-R-L-L-

R-D-A;

(SEQ ID NO: 88)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-V-R-

K-R-L-L-R-D-A;

(SEQ ID NO: 89)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-

R-N-V-R-K-R-L-L-R-D-A;

(SEQ ID NO: 90)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-

A-S-H-L-R-N-V-R-K-R-L-L-R-D-A;

(SEQ ID NO: 91)

K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-M-R-K-R-L-L-R-D-A;

(SEQ ID NO: 92)

K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-M-R-K-R-L-L-

R-D-A;

(SEQ ID NO: 93)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-M-R-

K-R-L-L-R-D-A;

(SEQ ID NO: 94)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-

R-N-M-R-K-R-L-L-R-D-A;

(SEQ ID NO: 95)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-

A-S-H-L-R-N-M-R-K-R-L-L-R-D-A;

(SEQ ID NO: 96)

K-K-K-K-L-R-A-R-M-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 97)

K-K-K-K-K-K-K-K-L-R-A-R-M-A-S-H-L-R-K-L-R-K-R-L-L-

R-D-A;

(SEQ ID NO: 98)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-A-R-M-A-S-H-L-R-K-L-R-

K-R-L-L-R-D-A;

(SEQ ID NO: 99)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-A-R-M-A-S-H-L-

R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 100)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-A-R-M-

A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;

(SEQ ID NO: 101)

K-K-K-K-L-R-V-R-L-S-S-H-L-R-K-L-R-K-R-L-M-R-D-A;

(SEQ ID NO: 102)

K-K-K-K-K-K-K-K-L-R-V-R-L-S-S-H-L-R-K-L-R-K-R-L-M-

R-D-A;

(SEQ ID NO: 103)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-S-S-H-L-R-K-L-R-

K-R-L-M-R-D-A;

(SEQ ID NO: 104)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-S-S-H-L-

R-K-L-R-K-R-L-M-R-D-A;

(SEQ ID NO: 105)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-

S-S-H-L-R-K-L-R-K-R-L-M-R-D-A;

(SEQ ID NO: 106)

K-K-K-K-L-R-S-R-L-A-S-H-L-R-K-L-R-K-R-L-M-R-D-A;

(SEQ ID NO: 107)

K-K-K-K-K-K-K-K-L-R-S-R-L-A-S-H-L-R-K-L-R-K-R-L-M-

R-D-A;

(SEQ ID NO: 108)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-S-R-L-A-S-H-L-R-K-L-R-

K-R-L-M-R-D-A;

(SEQ ID NO: 109)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-S-R-L-A-S-H-L-

R-K-L-R-K-R-L-M-R-D-A;

(SEQ ID NO: 110)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-S-R-L-

A-S-H-L-R-K-L-R-K-R-L-M-R-D-A;

(SEQ ID NO: 116)

K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-M-R-K-R-L-M-R-D-A;

(SEQ ID NO: 117)

K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-M-R-K-R-L-M-

R-D-A;

(SEQ ID NO: 118)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-M-R-

K-R-L-M-R-D-A;

(SEQ ID NO: 119)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-

R-K-M-R-K-R-L-M-R-D-A;

(SEQ ID NO: 120)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-

A-S-H-L-R-K-M-R-K-R-L-M-R-D-A;

(SEQ ID NO: 121)

K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-L-P-K-R-L-L-R-D-A;

(SEQ ID NO: 122)

K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-L-P-K-R-L-L-

R-D-A;

(SEQ ID NO: 123)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-L-P-

K-R-L-L-R-D-A;

(SEQ ID NO: 124)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-

R-N-L-P-K-R-L-L-R-D-A;

(SEQ ID NO: 125)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-

A-S-H-L-R-N-L-P-K-R-L-L-R-D-A;

(SEQ ID NO: 131)

K-K-K-K-L-R-L-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-L;

(SEQ ID NO: 132)

K-K-K-K-K-K-K-K-L-R-L-R-L-A-S-H-L-R-K-L-R-K-R-L-L-

R-D-L;

(SEQ ID NO: 133)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-L-R-L-A-S-H-L-R-K-L-R-

K-R-L-L-R-D-L;

(SEQ ID NO: 134)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-L-R-L-A-S-H-L-

R-K-L-R-K-R-L-L-R-D-L;

(SEQ ID NO: 135)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-L-R-L-

A-S-H-L-R-K-L-R-K-R-L-L-R-D-L;

(SEQ ID NO: 136)

K-K-K-K-L-R-V-R-L-A-N-H-L-R-K-L-R-K-R-L-L-R-D-L;

(SEQ ID NO: 137)

K-K-K-K-K-K-K-K-L-R-V-R-L-A-N-H-L-R-K-L-R-K-R-L-L-

R-D-L;

(SEQ ID NO: 138)

K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-N-H-L-R-K-L-R-

K-R-L-L-R-D-L;

(SEQ ID NO: 139)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-N-H-L-

R-K-L-R-K-R-L-L-R-D-L; and

(SEQ ID NO: 140)

K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-

A-N-H-L-R-K-L-R-K-R-L-L-R-D-L.

15. A method of treating a brain disorder in a subject, the method comprising administering to the subject a complex, or a pharmaceutically acceptable salt thereof, comprising a biologically active agent associated with a carrier peptide, wherein the carrier peptide consists of the sequence:

X n —[B] m

wherein:

X is a hydrophilic amino acid;

B is a blood-brain barrier agent of the sequence L-R-X1-R-X2-X3-X4-H-L-R-X5-X6-X7-K-R-L-X8-R-D-X9 (SEQ ID NO:29), wherein:

X1 is selected from the group consisting of A, L, S, and V;

X2 is selected from the group consisting of L and M;

X3 is selected from the group consisting of A and S;

X4 is selected from the group consisting of N, S, and T;

X5 is selected from the group consisting of K and N;

X6 is selected from the group consisting of L, M, and V;

X7 is selected from the group consisting of R and P;

X8 is selected from the group consisting of L and M; and

X9 is selected from the group consisting of A and L;

n is an integer from 4 to 50; and

m is integer from 1 to 3.

16. The method of claim 15 , wherein the brain disorder is chosen from: meningitis, epilepsy, multiple sclerosis, neuromyelitis optica, late-stage neurological trypanosomiasis, Parkinson's, progressive multifocal leukoencephalopathy, De Vivo disease, Alzheimer's disease, HIV Encephalitis, and cancer.

17. A method of imaging the central nervous system of a subject, the method comprising administering to the subject a complex, or a pharmaceutically acceptable salt thereof, comprising an imaging agent associated with a carrier peptide, wherein the carrier peptide consists of the sequence:

X n —[B] m

wherein:

X is a hydrophilic amino acid;

B is a blood-brain barrier agent of the sequence L-R-X1-R-X2-X3-X4-H-L-R-X5-X6-X7-K-R-L-X8-R-D-X9 (SEQ ID NO:29), wherein:

X1 is selected from the group consisting of A, L, S, and V;

X2 is selected from the group consisting of L and M;

X3 is selected from the group consisting of A and S;

X4 is selected from the group consisting of N, S, and T;

X5 is selected from the group consisting of K and N;

X6 is selected from the group consisting of L, M, and V;

X7 is selected from the group consisting of R and P;

X8 is selected from the group consisting of L and M; and

X9 is selected from the group consisting of A and L;

n is an integer from 4 to 50; and

m is integer from 1 to 3; and

imaging the central nervous system of the subject.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 27, 2019

From: CURRAN, GEOFFRY L.; SARKAR, GOBINDA; PODUSLO, JOSEPH F.; JENKINS, ROBERT B.; LOWE, VAL J.; MAHLUM, ERIC W.

To: MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH

Reel/Frame 049607/0283 →

Continuity (4)

Continuation 14281389 · May 19, 2014

Division 13383710

Provisional Application 61225412 · Jul 14, 2009

Related Publication 20170145076A1 · May 25, 2017