The present invention relates to antibodies and related molecules that specifically bind to C3a Receptor. Such antibodies have uses, for example, in the prevention and treatment of asthma, allergy, inflammatory and immune disorders. The invention also relates to nucleic acid molecules encoding anti-C3a Receptor antibodies, vectors and host cells containing these nucleic acids, and methods for producing the same. The present invention relates to methods and compositions for preventing, detecting, diagnosing, treating or ameliorating a disease or disorder, especially asthma, allergy, inflammatory and immune disorders, comprising administering to an animal, preferably a human, an effective amount of one or more antibodies or fragments or variants thereof, or related molecules, that specifically bind to C3a Receptor.
Activation of the complement cascade results in the generation of proinflammatory mediators such as the anaphylotoxins C3a, C4a and C5a. The receptor for C3a is a seven transmembrane G protein coupled receptor protein. The C3a Receptor shares 40% homology with C5a Receptor. The C3a Receptor also contains an unusually large second extracellular loop between transmembrane segments 4 and 5, which contains the major binding site for C3a. A large portion of the second extracellular loop may be mutated without affecting C3a function at the receptor. This data coupled with the knowledge that the second extracellular loop is conserved across species leaves open the possibility that there may be another as yet unidentified ligand for C3a (Chao et al., (1999) J. Biol. Chem. 274 9721-9728). C3aR is expressed predominantly on granulocytes and monocytes, but has also been found in lung, spleen, heart, placenta, spinal cord and brain, suggesting an important role in inflammatory reactions in tissues. High levels of expression are found on eosinophils and the mast cell line HMC-1. C3a Receptor expression is also expressed on airway smooth muscle cells. C3a is known to activate and induce chemotaxis of human eosinophils and mast cells (Daffern, P. J. et al., (1995) J. Exp. Med. 181:2119-2127; Nilsson, G. et al., (1996) J. Immunol. 1693-1698; and Stimler-Gerard, N. P., and Galli, S. J., (1987) J. Immunol. 138:1908-13) as well as to induce contraction of human lung parenchymal strips (Stimler, N. P. et al, Platelet Activating Factor, eds. Benveniste, J. and Amoux, B. Elsevier, Amsterdam, 1983 pp. 195-203).
Expression of C3a Receptor in airway smooth muscle cells and on cells associated with allergic responses, suggested that c3A receptor may be involved in the pathophysiology of asthma and allergy. Asthma is a chronic inflammatory disease of the airways and lung mucosa with a strong correlation to atopy and acquired (IgE) immunity. However, many features of bronchial asthma, such as smooth muscle contraction, mucus secretion and recruitment of inflammatory cells, are consistent with the actions of complement anaphylatoxins, in particular C3a and C5a. The anaphylatoxins C3a and C5a are liberated as activation byproducts and are potent pro-inflammatory mediators that bind to specific cell surface receptors and cause leukocyte activation, smooth muscle contraction and vascular permeability. Genetic deletion of the C3a Receptor protects against the changes in lung physiology seen after allergen challenge. Furthermore, human asthmatics develop significant levels of C3a following intra-pulmonary deposition of allergen, but not saline. (Humbles et al., (2000) Nature 406:998-1001).
Because of the involvement of the C3a Receptor in the promotion of the asthmatic response and other allergic and inflammatory responses in general, there is a clear need in the art for agents that can be used to monitor the expression of C3a Receptor and/or modulate the biological activities of C3a Receptor.