GMP LPS

Lipopolysaccharide List™ HPT™ from Escherichia coli Type O113

For many years, List Biological Laboratories (List Labs) has manufactured various types of Lipopolysaccharides (LPS, a.k.a. endotoxin) as reagent grade material, that are for research use only. List Labs has also developed a purification method that is compliant with cGMP guidelines according to 21 CFR 211. The purification method yields a product that is sterilizable by filtration and free of protein and nucleic acids. This GMP compliant LPS drug product is available to clinical researchers with Investigational New Drug (IND) applications submitted to the Food and Drug Administration (FDA).

Why type O113?

The bacterial strain used to produce GMP LPS is E. coli O113:H10:K-. This designates the O Antigen type (O113) of the Lipopolysaccharide (LPS), the flagella antigen type (H10) and capsule negative (K-). It is the type that was used for the National Reference Endotoxin1 and for the Second International Standard for Endotoxin.2 The intended use of these standards is as reference calibrants for bacterial endotoxin testing, such as pyrogenicity in rabbits or limulus amoebocyte lysate (LAL) assays. LPS type O113 has the structure typical of enteric bacteria and has the pro-inflammatory activity of a TLR-4 agonist.3

What's the benefit of using List Labs GMP LPS?

The cost of custom manufacturing of a GMP product is quite high when considering the small amount of LPS that is required for clinical trials. In addition, development costs for a custom product can not only be high, but also time consuming. Because List Labs has GMP LPS in stock, there is no time delay, and the cost is associated only with the needed amount of product and not the entire batch of material produced.

A Drug Master File has been submitted to FDA and has been accepted, also eliminating time delays due to regulatory issues.

How to purchase GMP LPS?

List Labs GMP LPS, Catalog #9433A, is only available for purchase directly from List Labs.

The minimum order quantity for domestic purchases is 10 vials at 1μg (mcg) per vial.

The MOQ for international shipments is 25 vials at 1μg (mcg) per vial.

Please view and sign the required indemnification agreement (view and download)

List Labs requires 50% upfront payment to reserve and process your order, the balance is invoiced upon shipment. List Labs will arrange the temperature-controlled transportation. Shipping costs will be included in the final invoice. Purchaser is responsible for paying all customs duties and taxes.

Contact us for more information or to order GMP LPS

How our GMP LPS is being used

This product is appropriate for researchers doing clinical work under an IND which has been, or will be, submitted to FDA prior to use in humans. US customers can request an authorizing cross reference letter to the drug master file allowing them to cite the DMF, thereby allowing for FDA review. Currently, this product is being used by major pharmaceutical companies and universities, as well as the NIH Clinical Center for human studies.

Endotoxin has been used to study a variety of conditions that can be modeled by an inflammatory challenge with endotoxin/lipopolysaccharide from E. coli type O113. Suffredini, et al, reported the effects of intravenous endotoxin and discussed its role in the study of experimental inflammation.4 Bridging studies evaluated the effects of LPS manufactured by List Labs, administered intravenously, and concluded that a lot produced by List Labs is safe and produced the expected acute self-limiting inflammatory responses including pro-inflammatory cytokine responses with the expected level of adverse effects.5,6,7,8

Endotoxin is used as an inflammatory challenge to study treatment modalities for a variety of conditions that can be induced, such as depression,9,10,11,12 lung inflammation13,14 and cardio-metabolic disease.15,16 Fullerton describes the use of endotoxin by IV challenge to reproducibly model acute or chronic inflammation and to study the effects of therapeutic interventions.17

By the inhalation route, LPS induces inflammation and dendritic cell maturation as a Toll-like receptor 4 (TLR4) ligand.18 Ex vivo preparation of experimental cancer vaccines have utilized LPS in the cocktail to mature dendritic cells.19,20

Production and Characterization

This product is highly purified and well characterized. It is provided as a sterile lyophilized product in 1% lactose, 0.1% PEG6000, and is currently in stock.

A Certificate of Analysis is provided at shipment that includes a GMP compliance statement, certificate of origin and BSE/TSE statement.

GMP LPS is produced compliant to US FDA Good Manufacturing Practices guidelines found in 21 CFR 211. Please consult your internal Regulatory groups prior to use in humans.

GMP Tetanus Product In Development

List Labs is developing a cGMP production method for tetanus toxoid. Tetanus toxoid is a valuable hapten carrier in a population previously vaccinated with Tetanus-Diphtheria (TD) or Tetanus-Diphtheria-Acellular Pertussis (Tdap) vaccines. Contact us if you would like to receive more information when it becomes available.

References:

Rudbach JA, Akiya FI, Elin RJ, Hochstein HD, Luoma MK, Milner ECB, Milner KC, Thomas KR, Preparation and Properties of a National Reference Endotoxin, J Clin Microbiol, 1976, 3(1):21-5, PMID: 1254700
Poole S, Dawson P, Gaines Das RE, Second International Standard for Endotoxin: Calibration in an International Collaborative Study, J Endotoxin Res, 1997, 4(3):221-31
Park BS, Lee J-O, Recognition of Lipopolysaccharide Pattern by TLR4 Complexes, Exp Mol Med, 2013, 45:e66, PMID: 24310172
Suffredini AF, Hochstein HD, McMahon FG, Dose-Related Inflammatory Effects of Intravenous Endotoxin in Humans: Evaluation of a New Clinical Lot of Escherichia coli O:113 Endotoxin, J Infect Dis, 1999, 179(5):1278-82, PMID: 10191237
Noveck RJ, Duke University, Dose-Related Inflammatory Effects of Intravenous Endotoxin in Humans, 2016, ClinicalTrials.gov, ID: NCT02789241
Noveck RJ, Guptill JT, Cohen-Wolkowiez M, Hauser BM, Suffredini AF, Dose-Related Inflammatory Effects of Intravenous Endotoxin in Humans: Evaluation of a New Clinical lot (CCRE Lot 94332B1) of Escherichia Coli O:113 Endotoxin (LPS), Clinical Pharmacology and Therapeutics, 2018, 103:S82-3
Gairhe S, Torabi-Parizi P, Ingram B, Karoly ED, Guptill J, Cohen-Wolkowiez M, Noveck RJ, Suffredini AF, A Dose-Related Hypermetabolic Phenotype Following High and Low Dose Intravenous Endotoxin Challenges in Healthy Volunteers, American Journal of Respiratory and Critical Care Medicine, 2018, 197:A1812
Torabi-Parizi P, Biancotto A, Fantoni G, Demirkale C, Guptill JT, Cohen-Wolkowiez M, Noveck RJ, Suffredini AF, Human Plasma Proteome Analysis Following Endotoxin Challenge Identifies New Proteins that Contribute to Molecular Phenotype of Innate Immunity, American Journal of Respiratory and Critical Care Medicine, 2018, 197:A4749
DellaGioia N, Hannestad J, A Critical Review of Human Endotoxin Administration as an Experimental Paradigm of Depression, Neurosci Biobehav Rev, 2010, 34(1):130-43, PMID: 19666048
Irwin M, University of California, Los Angeles, Sleep and Healthy Aging Research for Depression (SHARE-D) Study (SHARE-D), 2017, ClinicalTrials.gov, ID: NCT03256760
Savitz J, Laureate Institute for Brain Research, Inc., Lipopolysaccharide (LPS) Challenge in Depression, 2017, ClinicalTrials.gov, ID: NCT03142919
Cho HJ, University of California, Los Angeles, Leucine for Depression Study (L-DEP), 2018, ClinicalTrials.gov, ID: NCT03557684
Janssen O, Schaumann F, Holz O, Lavae-Mokhtari B, Welker L, Winkler C, Biller H, Krug N, Hohlfeld JM, Low-Dose Endotoxin Inhalation in Healthy Volunteers – A Challenge Model for Early Clinical Drug Development, BMC Pulm Med, 2013, 13:19, PMID: 23537365
Dillon MA, Harris B, Hernandez ML, Zou B, Reed W, Bromberg PA, Devlin RB, Diaz-Sanchez D, Kleeberger S, Zhou H, Lay JC, Alexis NE, Peden DB, Enhancement of Systemic and Sputum Granulocyte Response to Inhaled Endotoxin in People with the GSTM1 Null Genotype, Occup Environ Med, 2011, 68(10):783-5, PMID: 21441173
Patel PN, Shah RY, Ferguson JF, Reilly MP, Human Experimental Endotoxemia in Modeling the Pathophysiology, Genomics and Therapeutics of Innate Immunity in Complex Cardiometabolic Diseases, Arterioscler Thromb Vasc Biol, 2015, 35(3):525-34, PMID: 25550206
Hernandez M, University of North Carolina, Chapel Hill, Effects of 20,000 EU of Clinical Center Reference Endotoxin (CCRE) Versus Placebo(ENDOHEART) (Endoheart), 2018, ClinicalTrials.gov, ID: NCT03623022
Fullerton JN, Segre E, De Maeyer RPH, Maini AAN, Gilroy DW, Intravenous Endotoxin Challenge in Healthy Humans: An Experimental Platform to Investigate and Modulate System Inflammation, J Vis Exp, 2016, 111:e53913, PMID: 27213711
Alexis NE, Lay JC, Almond M, Bromberg PA, Patel DD, Peden DB, Acute LPS Inhalation in Healthy Volunteers Induces Dendritic Cell Maturation In Vivo, J Allergy Clin Immunol, 2005, 115(2):345-50, PMID: 15696093
Wood LV, Fojo A, Roberson BD, Hughes MS, Dahut W, Gulley JL, Madan RA, Arlen PM, Sabatino M, Stroncek DF, Castiello L, Trepel JB, Lee M-J, Parnes HL, Steinberg SM, Terabe M, Wilkerson J, Pastan I, Berzofsky JA, TARP Vaccination is Associated with Slowing in PSA Velocity and Decreasing Tumor Growth Rates in Patients with Stage D0 Prostate Cancer, Oncoimmunology, 2016, 5(8):e1197459, PMID: 27622067
Castiello L, Sabatino M, Ren J, Terabe M, Khuu H, Wood LV, Berzofsky JA, Stroncek DF, Expression of CD14, IL-10 and Tolerogenic Signature in Dendritic Cells Inversely Correlate with Clinical and Immunological Response to TARP Vaccination in Prostate Cancer Patients, Clin Cancer Res, 2017, 23(13):3352-64, PMID: 28073842