A two part, phase 1, randomised, placebo-controlled, single ascending dose study to evaluate the safety, tolerability and pharmacokinetics of GBR 830 in adult healthy volunteers (Part 1) and a randomised, placebo-controlled, pharmacodynamic study to evaluate the effect of single dose of GBR 830 on vaccination response in adult, healthy volunteers (Part 2)

GBR 830 is a new investigational compound that may eventually be used for the
treatment of inflammatory responses in several autoimmune diseases. An
autoimmune disease is an illness that occurs when the body tissues are attacked
by its own immune system. This occurs for example in rheumatoid arthritis
patients.

Antibodies are produced by our own body for host defense against for example
bacteria and viruses. However, antibodies can also be prepared in a custom made
way by pharmaceutical companies, so that they can be used for medical research
and various therapeutic applications. GBR 830 is an antibody designed to
specifically recognize, bind and block the function of the OX40 receptor on T
cells. A receptor is a protein on the cell surface that can initiate a cell
response when a signal molecule binds to the receptor. T cells are a specific
type of white blood cells that play an important role in immune responses.

Because GBR 830 is a protein, the body may recognize the drug as foreign. As a
result an immune response can occur, for example by making antibodies. The
ability of a compound to elicit an immune response is called immunogenicity.
The production of antibodies towards the medication leads to reduced efficacy
of the medical product. Therefore it will be investigated whether antibodies
are produced after administration of GBR 830.

This is the first time that GBR 830 is being given to humans.

The purpose of this study is to investigate to what extent GBR 830 is
tolerated. It will also be investigated how quickly and to what extent GBR 830
is absorbed and eliminated from the body (this is called pharmacokinetics) and
to what extent the body produces antibodies towards GBR 830 (immunogenicity).

In Part 2 of the study it will also be investigated what the effect of GBR 830
is on T cell dependent immune responses (this is called pharmacodynamics).

This study will be performed in 52 healthy male and female volunteers, divided
over 5 groups.

Part 1 will be performed in 32 healthy male and female volunteers, divided over
4 groups with 8 volunteers per group.

Part 2 will be performed in 20 healthy male and female volunteers, divided over
2 groups with 10 volunteers per group.

Part 1:
The actual study will consist of 1 period during which you will stay in the
clinical research center in Groningen for 6 days (5 nights). The volunteer will
have to come back to the clinical research center in Groningen for 8 additional
short visits.

Part 2:
The actual study will consist of 1 period during which you will stay in the
clinical research center in Groningen for 4 days (3 nights). The volunteer will
have to come back to the clinical research center in Groningen for 7 additional
short visits.

Part 1:
During the study the volunteer will receive GBR 830 or placebo by an
intravenous infusion of 1 hour, approximately 1 hour after completing a light
breakfast.

Part 2:
On Day 1 of the study the volunteer will receive GBR 830 or placebo by an
intravenous infusion of 1 hour, approximately 1 hour after completing a light
breakfast.
On Day 2 the volunteer will receive 1 intramuscular injection with KLH, 1
intramuscular injection with TT, and 1 intradermal injection with Candida.

Part 1 and 2:
All potential drugs cause adverse events; the extent to which this occurs
differs. As GBR 830 will be administered to humans for the first time in this
study and blocking of the OX40 receptor in humans using medication has never
been done before, adverse effects of GBR 830 in humans have not been reported
to date. However, GBR 830 has been studied in animals. In animals no
abnormalities were observed and the study medication was well tolerated.
Development of a hypersensitivity reaction to GBR 830 may occur and you may
become more susceptible to infections.

Part 2:
Local reactions to an injection with Candida can include redness, swelling,
itching, discoloration of the skin and excoriation of the skin around the
injection site. These reactions usually subside within a few days the after
injection. Sometimes, skin discoloration may persist for several weeks.
Progression of the DTH reaction to vesiculation, ulceration and death of tissue
are possible.

Adverse effects that may occur after an injection with KLH include redness and
swelling at the site of injection. If the volunteer is allergic to KLH an
allergic reaction and redness of the skin can occur.

Adverse effects that may occur after an injection with TT include pain, redness
and swelling at the site of injection. Other adverse effects that may occur are
fever, malaise (feeling of discomfort