Background/Purpose: Antagonism of the CD28 costimulation receptor is thought to block T-cell
activation, making this a promising target for the treatment of many autoimmune
diseases, including systemic lupus erythematosus. Given the cytokine storm seen
with the CD28 agonist TGN1412,1 it is
important to cautiously characterize the clinical profile of agents targeting
CD28. Furthermore, evaluating target engagement and immunosuppression is
critical to establishing proof of mechanism before testing in patients. Here,
we report the pharmacokinetics (PK), pharmacodynamics
(PD) and safety profile of a novel anti-CD28 domain antibody (dAb) from 2 Phase
I studies in healthy subjects. Methods: Minimal anticipated biological effect level
(MABEL) approach was used to select a 0.01 mg starting dose in the single
ascending dose (SAD) study. In this double-blind first-in-human study, 9
subjects/panel were randomized to 9 IV (0.01–100 mg), 3 SC (9–50 mg) or placebo
panels. Subsequently, a keyhole limpet hemocyanin (KLH) challenge was performed
in 16 subjects/panel, who received 1 of 3 IV doses (9–100 mg) or placebo. In a
double-blind multiple ascending dose (MAD) study, subjects received 1 of 3
active SC treatments (6.25 mg 2x/month, 12.5 mg weekly or 37.5 mg weekly) or
placebo. PK, PD and safety were assessed. Results: A total of 180 subjects were treated
and 169 completed the SAD/MAD studies. The PK of anti-CD28 was linear after IV infusion
and SC administration, such that C_max and AUC_(INF)
increased dose proportionally. Bioavailability after SC administration was
estimated at 68.2%. The half-life was comparable for both administration routes
(5–7 days). High levels (≥80%) of receptor
occupancy were maintained for ≥2 weeks at doses of ≥9 mg (IV and
SC) in SAD and throughout the dosing interval in MAD. Single IV doses of ≥9
mg anti-CD28 inhibited antibody production against KLH for 2 weeks,
demonstrating immunosuppressive activity (Figure). No significant serum
cytokine changes nor any clinically relevant changes in T/B/natural killer cell
numbers were observed in SAD or MAD. There was a low incidence of detectable
anti-drug antibodies (≤16.7% in each dose group); no immunogenicity
responses were persistent, with no impact on drug clearance nor correlation to
AEs. The most commonly reported AEs were headache (SAD) and infections (MAD),
which were study drug-related but did not show dose dependency.

Conclusion: The PK of SC anti-CD28 is favorable, with high bioavailability and the ability to maintain serum concentrations over
a 2-week dosing interval. Following
IV and SC administration, anti-CD28 was safe at all doses studied, without
evidence of cytokine release. Anti-CD28 saturates the target receptor resulting
in KLH response inhibition. The observed immunosuppressive activity indicates
that anti-CD28 has potential to show clinical activity in the treatment of
autoimmune disease.

1.   
Suntharalingam G, et
al. N Engl J Med 2006;355:1018–28.