Potent neutralizing anti-CD1d antibody reduces lung cytokine release in primate asthma model.
CD1d is a receptor on antigen-presenting cells involved in triggering cell populations, particularly natural killer T (NKT) cells, to release high levels of cytokines. NKT cells are implicated in asthma pathology and blockade of the CD1d/NKT cell pathway may have therapeutic potential. We developed a potent anti-human CD1d antibody (NIB.2) that possesses high affinity for human and cynomolgus macaque CD1d (KD ∼100 pM) and strong neutralizing activity in human primary cell-based assays (IC50 typically <100 pM). By epitope mapping experiments, we showed that NIB.2 binds to CD1d in close proximity to the interface of CD1d and the Type 1 NKT cell receptor β-chain. Together with data showing that NIB.2 inhibited stimulation via CD1d loaded with different glycolipids, this supports a mechanism whereby NIB.2 inhibits NKT cell activation by inhibiting Type 1 NKT cell receptor β-chain interactions with CD1d, independent of the lipid antigen in the CD1d antigen-binding cleft. The strong in vitro potency of NIB.2 was reflected in vivo in an Ascaris suum cynomolgus macaque asthma model. Compared with vehicle control, NIB.2 treatment significantly reduced bronchoalveolar lavage (BAL) levels of Ascaris-induced cytokines IL-5, IL-8 and IL-1 receptor antagonist, and significantly reduced baseline levels of GM-CSF, IL-6, IL-15, IL-12/23p40, MIP-1α, MIP-1β, and VEGF. At a cellular population level NIB.2 also reduced numbers of BAL lymphocytes and macrophages, and blood eosinophils and basophils. We demonstrate that anti-CD1d antibody blockade of the CD1d/NKT pathway modulates inflammatory parameters in vivo in a primate inflammation model, with therapeutic potential for diseases where the local cytokine milieu is critical.
a Teva Pharmaceuticals Australia Pty. Ltd. ; North Ryde , NSW Australia.
Jonathan
J
Nambiar
Adam W
AW
Clarke
Doris
D
Shim
David
D
Mabon
Chen
C
Tian
Karolina
K
Windloch
Chris
C
Buhmann
Beau
B
Corazon
Matilda
M
Lindgren
Matthew
M
Pollard
Teresa
T
Domagala
Lynn
L
Poulton
Anthony G
AG
Doyle
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology*; D055610:Antigens, CD1d / Q000276:immunology*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008252:Macaca fascicularis; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D055611:Natural Killer T-Cells / Q000276:immunology / Q000473:pathology
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D055610:Antigens, CD1d
AHR, airway hyper-reactivity; APC, antigen-presenting cell; AUC, area under the curve; BAL, broncho-alveolar lavage; BSA, bovine serum albumin; CHO, Chinese hamster ovary; ELISA, enzyme-linked immunosorbent assay; G-CSF, granulocyte colony stimulating fac; CD1d, NKT cell, antibody, asthma, cytokine