WHO International Standards and Reference Preparations for Cytokines and Growth factors

Amanda E. I Proudfoot1 and Meenu Wadhwa2*

1ICIS Standards Committee Chair, and 2Cytokine & Growth Factors Section, Biotherapeutics Group, National Institute for Biological Standards and Control (NIBSC), Medicines and Healthcare products Regulatory Agency,Hertfordshire, UK

* Correspondence: [email protected]

The ability to quantify the activity of cytokines is an essential part of experimental and clinical investigation and is largely dependent upon the availability of suitable cytokine standards and reference reagents. The International Cytokine and Interferon Society (ICIS) Standards Committee was established to make recommendations regarding interferon and cytokine standards and standardization to the ICIS membership, and thereby to the international cytokine scientific community. The Committee works closely with the World Health Organization (WHO), the National Institute for Biological Standards and Control (NIBSC), the U.S. National Institutes of Health (NIH), the Biodefense and Emerging Infections Resources Repository (BEI Resources), pharmaceutical manufacturers, and regulatory agencies. The Committee includes members from several of these organizations. The role that the Committee plays as a source of information and recommendations to the ICIS membership, and to the international cytokine scientific community as a whole, is very much dependent upon suitable standards and reference materials being made available by the NIBSC. Similarly, the Standardization and Nomenclature Committee of the ICIS reviews the need for cytokine standards and their usage. With the expanding role of cytokines and growth factors in the development and manufacture of biotechnology derived products e.g., monoclonal antibodies targeting cytokines/growth factors, biosimilar medicines, cell and/or gene therapy products, the need for suitable standards is increasing.

The accompanying Table lists WHO International Standards (IS), WHO reference reagents (WRR) and other cytokine and growth factor standards available from the NIBSC. ISs and WRRs are publicly available reference standards with defined units (International Unit for IS) established by the WHO Expert Committee on Biological Standardization. Lyophilised and formulated to ensure long term stability, they serve as ‘primary’ standards for bioactivity and for calibration of secondary reference standards. The use of IS and WRR to calibrate commercially available or laboratory made reagents including immunoassays where feasible as per WHO recommendations facilitates comparisons of data between assays, different laboratories, and individual studies allowing global harmonisation.

Table 1. Cytokine and growth factor standards and reference reagents available from the National Institute for Biological Standards and Control

A wide range of WHO International Biological Standards and reference materials are available for the calibration of assays of therapeutic substances and immunoassays and bioassays used in basic research.  These materials are available from Standards Processing Division, National Institute for Biological Standards and Control (NIBSC), Blanche Lane, South Mimms, Potters Bar, Herts EN6 3QG, UK.  The NIBSC does not charge for these materials, however there is a handling charge to cover the costs of administration, storage, and dispatch.  The handling charge is currently £120 per ampoule. A comprehensive catalogue of reference materials is available from the above address or can be accessed online via the NIBSC website (www.nibsc.org/products).

Human Cytokine Standards and Reference Reagents

Preparation1

Product Code

Status2

Interleukin 1 alpha

Interleukin 1 beta

Interleukin 2

Interleukin 3

Interleukin 4

Interleukin 5

Interleukin 6

Interleukin 7

Interleukin 8

Interleukin 9

Interleukin 10

Interleukin 11

Interleukin 12

Interleukin 13

Interleukin 15

Interleukin 17

Interleukin 18

M-CSF

G-CSF

G-CSF(pegylated)

GM-CSF

Leukemia inhibitory factor

Oncostatin M

Stem cell factor

Flt 3 ligand

Bone morphogenetic protein-2

RANTES

MCP-1

GRO-alpha

IFN alpha leukocyte

IFN alpha 1 (D)

IFN alpha 1/8

IFN alpha 2a

IFN alpha 2b

IFN alpha 2c

IFN alpha n1 lymphoblastoid

IFN alpha n3 leukocyte

IFN alpha consensus

IFN omega

IFN beta

IFN beta ser17

IFN beta fibroblast

IFN gamma

IFN gamma leukocyte

IFN lambda1

TGF beta 1

TGF beta 2

TGF beta 3

Thrombopoietin

TNF alpha

TNF beta

TRAIL

86/632

86/680

86/500

91/510

88/656

90/586

89/548

90/530

89/520

91/678

93/722

92/788

95/544

94/622

95/554

01/420

03/200

89/512

09/136

12/188

88/646

93/562

93/564

91/682

96/532

93/574

92/520

92/794

92/722

94/784

83/514

95/572

95/650

95/566

95/580

95/568

95/574

94/786

94/754

00/572

00/574

00/576

87/586

82/587

10/176

89/514

90/696

09/234

03/124

12/154

87/640

04/166

1st IS

1st IS

2nd IS

1st IS

1st IS

WRR

1st IS

WRR

1st IS

WRR

WRR

WRR

WRR

WRR

WRR

WRR

WRR

1st IS

2nd IS

1st IS

1st IS

WRR

WRR

WRR

WRR

WRR

RR

RR

RR

1st IS

1st IS

1st IS

2nd IS

2nd IS

1st IS

2nd IS

1st IS

1st IS

1st IS

3rdIS

RR

RR

RR

BWS

WRR

RR

RR

1st IS

RR

3rd IS

WRR

WRR

Human Growth Factor Standards and Reference Reagents

Preparation1 Product Code Status2
Basic Fibroblast Growth Factor 90/712 1st IS
Brain-derived neurotrophic factor 96/534 WRR
Ciliary Neurotrophic Factor 94/684 WRR
Epidermal Growth Factor 91/530 1st IS
Epidermal Growth Factor (1-52) 91/550 WRR
Hepatocyte Growth Factor 96/564 WRR
Hepatocyte Growth Factor precursor 96/556 1st IS
Keratinocyte Growth Factor 03/150 WRR
Keratinocyte Growth Factor (24-163) 03/148 WRR
Leptin 97/594 1st IS
Nerve Growth Factor 93/556 WRR
Neurotrophin-3 98/718 RR
Platelet derived Growth factor BB 94/728 1st IS
Vascular Endothelial Growth Factor 165 02/286 WRR

Murine Cytokine Standards and Reference Reagents

Preparation1

Product Code

Status2

GM-CSF 91/658 RR
Interleukin1- a 93/672 RR
Interleukin1-b 93/668 RR
Interleukin 2 93/566 RR
Interleukin 3 91/662 RR
Interleukin 4 91/656 RR
Interleukin 6 93/730 RR
Interleukin 7 93/740 RR
Interleukin 9 93/504 RR
Leptin 97/626 IS
TNF-a 88/532 RR

Standards for Cytokine Antagonists

Preparation1 Product Code Status2
Etanercept 13/204 1st IS
Infliximab 16/170 1st IS

1All preparations listed above are rDNA derived unless specified;

2 IS – International Standard; WRR – WHO Reference Reagent; RR – NIBSC Reference Reagent; BWS – British Working standard; WS – Working standard

About the National Institute for Biological Standards and Control

The National Institute for Biological Standards and Control (NIBSC) is a global leader in the standardisation and control of biological medicines, playing a major role in assuring the quality of biological medicines worldwide.

NIBSC is a centre of the Medicines and Healthcare products Regulatory Agency which also includes CPRD and MHRA. The Medicines and Healthcare products Regulatory Agency is an executive agency of the Department of Health.

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