Preclinical in vitro and in vivo characterization of the fully human monoclonal IgM antibody KBPA101 specific for Pseudomonas aeruginosa serotype IATS-O11

Michael P Horn; Adrian W Zuercher; Martin A Imboden; Michael P Rudolf; Hedvika Lazar; Hong Wu; Niels Høiby; Stefanie C Fas; Alois B Lang

doi:10.1128/AAC.01142-09

Preclinical in vitro and in vivo characterization of the fully human monoclonal IgM antibody KBPA101 specific for Pseudomonas aeruginosa serotype IATS-O11

Michael P Horn, Adrian W Zuercher, Martin A Imboden, Michael P Rudolf, Hedvika Lazar, Hong Wu, Niels Høiby, Stefanie C Fas, Alois B Lang

Department of Immunology and Microbiology

39 Citations (Scopus)

Abstract

Pseudomonas aeruginosa infection in ventilator-associated pneumonia is a serious and often life-threatening complication in intensive care unit patients, and new treatment options are needed. We used B-cell-enriched peripheral blood lymphocytes from a volunteer immunized with a P. aeruginosa O-polysaccharide- toxin A conjugate vaccine to generate human hybridoma cell lines producing monoclonal antibodies specific for individual P. aeruginosa lipopolysaccharide serotypes. The fully human monoclonal antibody secreted by one of these lines, KBPA101, is an IgM/κ antibody that binds P. aeruginosa of International Antigenic Typing System (IATS) serotype O11 with high avidity (5.81 × 10⁷ M^-1 ± 2.8 × 107 M^-1) without cross-reacting with other serotypes. KBPA101 specifically opsonized the P. aeruginosa of IATS O11 serotype and mediated complement-dependent phagocytosis in vitro by the human monocyte-like cell line HL-60 at a very low concentration (half-maximal phagocytosis at 0.16 ng/ml). In vivo evaluation of KBPA101 demonstrated a dose-response relationship for protection against systemic infections in a murine burn wound sepsis model, where 70 to 100% of animals were protected against lethal challenges with P. aeruginosa at doses as low as 5 μg/animal. Furthermore, a high efficacy of KBPA101 in protection from local respiratory infections in an acute lung infection model in mice was demonstrated. Preclinical toxicology evaluation on human tissue, in rabbits, and in mice did not indicate any toxicity of KBPA101. Based on these preclinical findings, the first human clinical trials have been initiated.

Original language	English
Journal	Antimicrobial Agents and Chemotherapy
Volume	54
Issue number	6
Pages (from-to)	2338-44
Number of pages	7
ISSN	0066-4804
DOIs	https://doi.org/10.1128/AAC.01142-09 https://doi.org/10.1128/AAC.01142-09
Publication status	Published - 1 Jun 2010

Keywords

Animals
Antibodies, Bacterial
Antibodies, Monoclonal
Antibody Affinity
Antibody Specificity
Base Sequence
Cell Line
Complement System Proteins
DNA Primers
Disease Models, Animal
HL-60 Cells
Humans
Hybridomas
Immunoglobulin M
Mice
Phagocytosis
Pneumonia, Bacterial
Pseudomonas Infections
Pseudomonas aeruginosa
Rabbits
Sepsis
Serotyping

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Horn, M. P., Zuercher, A. W., Imboden, M. A., Rudolf, M. P., Lazar, H., Wu, H., Høiby, N., Fas, S. C., & Lang, A. B. (2010). Preclinical in vitro and in vivo characterization of the fully human monoclonal IgM antibody KBPA101 specific for Pseudomonas aeruginosa serotype IATS-O11. Antimicrobial Agents and Chemotherapy, 54(6), 2338-44. https://doi.org/10.1128/AAC.01142-09, https://doi.org/10.1128/AAC.01142-09

Preclinical in vitro and in vivo characterization of the fully human monoclonal IgM antibody KBPA101 specific for Pseudomonas aeruginosa serotype IATS-O11. / Horn, Michael P; Zuercher, Adrian W; Imboden, Martin A et al.

In: Antimicrobial Agents and Chemotherapy, Vol. 54, No. 6, 01.06.2010, p. 2338-44.

Research output: Contribution to journal › Journal article › Research › peer-review

Horn, MP, Zuercher, AW, Imboden, MA, Rudolf, MP, Lazar, H, Wu, H, Høiby, N, Fas, SC & Lang, AB 2010, 'Preclinical in vitro and in vivo characterization of the fully human monoclonal IgM antibody KBPA101 specific for Pseudomonas aeruginosa serotype IATS-O11', Antimicrobial Agents and Chemotherapy, vol. 54, no. 6, pp. 2338-44. https://doi.org/10.1128/AAC.01142-09, https://doi.org/10.1128/AAC.01142-09

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title = "Preclinical in vitro and in vivo characterization of the fully human monoclonal IgM antibody KBPA101 specific for Pseudomonas aeruginosa serotype IATS-O11",

abstract = "Pseudomonas aeruginosa infection in ventilator-associated pneumonia is a serious and often life-threatening complication in intensive care unit patients, and new treatment options are needed. We used B-cell-enriched peripheral blood lymphocytes from a volunteer immunized with a P. aeruginosa O-polysaccharide- toxin A conjugate vaccine to generate human hybridoma cell lines producing monoclonal antibodies specific for individual P. aeruginosa lipopolysaccharide serotypes. The fully human monoclonal antibody secreted by one of these lines, KBPA101, is an IgM/κ antibody that binds P. aeruginosa of International Antigenic Typing System (IATS) serotype O11 with high avidity (5.81 × 107 M-1 ± 2.8 × 107 M-1) without cross-reacting with other serotypes. KBPA101 specifically opsonized the P. aeruginosa of IATS O11 serotype and mediated complement-dependent phagocytosis in vitro by the human monocyte-like cell line HL-60 at a very low concentration (half-maximal phagocytosis at 0.16 ng/ml). In vivo evaluation of KBPA101 demonstrated a dose-response relationship for protection against systemic infections in a murine burn wound sepsis model, where 70 to 100% of animals were protected against lethal challenges with P. aeruginosa at doses as low as 5 μg/animal. Furthermore, a high efficacy of KBPA101 in protection from local respiratory infections in an acute lung infection model in mice was demonstrated. Preclinical toxicology evaluation on human tissue, in rabbits, and in mice did not indicate any toxicity of KBPA101. Based on these preclinical findings, the first human clinical trials have been initiated.",

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T1 - Preclinical in vitro and in vivo characterization of the fully human monoclonal IgM antibody KBPA101 specific for Pseudomonas aeruginosa serotype IATS-O11

AU - Horn, Michael P

AU - Zuercher, Adrian W

AU - Imboden, Martin A

AU - Rudolf, Michael P

AU - Lazar, Hedvika

AU - Wu, Hong

AU - Høiby, Niels

AU - Fas, Stefanie C

AU - Lang, Alois B

PY - 2010/6/1

Y1 - 2010/6/1

N2 - Pseudomonas aeruginosa infection in ventilator-associated pneumonia is a serious and often life-threatening complication in intensive care unit patients, and new treatment options are needed. We used B-cell-enriched peripheral blood lymphocytes from a volunteer immunized with a P. aeruginosa O-polysaccharide- toxin A conjugate vaccine to generate human hybridoma cell lines producing monoclonal antibodies specific for individual P. aeruginosa lipopolysaccharide serotypes. The fully human monoclonal antibody secreted by one of these lines, KBPA101, is an IgM/κ antibody that binds P. aeruginosa of International Antigenic Typing System (IATS) serotype O11 with high avidity (5.81 × 107 M-1 ± 2.8 × 107 M-1) without cross-reacting with other serotypes. KBPA101 specifically opsonized the P. aeruginosa of IATS O11 serotype and mediated complement-dependent phagocytosis in vitro by the human monocyte-like cell line HL-60 at a very low concentration (half-maximal phagocytosis at 0.16 ng/ml). In vivo evaluation of KBPA101 demonstrated a dose-response relationship for protection against systemic infections in a murine burn wound sepsis model, where 70 to 100% of animals were protected against lethal challenges with P. aeruginosa at doses as low as 5 μg/animal. Furthermore, a high efficacy of KBPA101 in protection from local respiratory infections in an acute lung infection model in mice was demonstrated. Preclinical toxicology evaluation on human tissue, in rabbits, and in mice did not indicate any toxicity of KBPA101. Based on these preclinical findings, the first human clinical trials have been initiated.

AB - Pseudomonas aeruginosa infection in ventilator-associated pneumonia is a serious and often life-threatening complication in intensive care unit patients, and new treatment options are needed. We used B-cell-enriched peripheral blood lymphocytes from a volunteer immunized with a P. aeruginosa O-polysaccharide- toxin A conjugate vaccine to generate human hybridoma cell lines producing monoclonal antibodies specific for individual P. aeruginosa lipopolysaccharide serotypes. The fully human monoclonal antibody secreted by one of these lines, KBPA101, is an IgM/κ antibody that binds P. aeruginosa of International Antigenic Typing System (IATS) serotype O11 with high avidity (5.81 × 107 M-1 ± 2.8 × 107 M-1) without cross-reacting with other serotypes. KBPA101 specifically opsonized the P. aeruginosa of IATS O11 serotype and mediated complement-dependent phagocytosis in vitro by the human monocyte-like cell line HL-60 at a very low concentration (half-maximal phagocytosis at 0.16 ng/ml). In vivo evaluation of KBPA101 demonstrated a dose-response relationship for protection against systemic infections in a murine burn wound sepsis model, where 70 to 100% of animals were protected against lethal challenges with P. aeruginosa at doses as low as 5 μg/animal. Furthermore, a high efficacy of KBPA101 in protection from local respiratory infections in an acute lung infection model in mice was demonstrated. Preclinical toxicology evaluation on human tissue, in rabbits, and in mice did not indicate any toxicity of KBPA101. Based on these preclinical findings, the first human clinical trials have been initiated.

KW - Animals

KW - Antibodies, Bacterial

KW - Antibodies, Monoclonal

KW - Antibody Affinity

KW - Antibody Specificity

KW - Base Sequence

KW - Cell Line

KW - Complement System Proteins

KW - DNA Primers

KW - Disease Models, Animal

KW - HL-60 Cells

KW - Humans

KW - Hybridomas

KW - Immunoglobulin M

KW - Mice

KW - Phagocytosis

KW - Pneumonia, Bacterial

KW - Pseudomonas Infections

KW - Pseudomonas aeruginosa

KW - Rabbits

KW - Sepsis

KW - Serotyping

U2 - 10.1128/AAC.01142-09

DO - 10.1128/AAC.01142-09

M3 - Journal article

C2 - 20308370

SN - 0066-4804

VL - 54

SP - 2338

EP - 2344

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

IS - 6

ER -

Preclinical in vitro and in vivo characterization of the fully human monoclonal IgM antibody KBPA101 specific for Pseudomonas aeruginosa serotype IATS-O11

Abstract

Keywords

UN SDGs

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