Methods and compositions for treating or preventing skin disorders using binding agents specific for prostate specific membrane antigen

#The invention relates to the use of a binding agent specific for prostate specific membrane antigen (PSMA) to treat or prevent a skin disorder, e.g., psoriasis.

#The skin is composed of the epidermis, an epithelial layer of ectodermal origin, and the dermis, a layer of connective tissue of mesodermal origin. See generally Fitzpatrick (1999) Dermatology in General Medicine, 5th ed., McGraw Hill. The junction of dermis and epidermis is mostly irregular, and projections of the dermis, known as papillae, interdigitate with evaginations of the epidermis known as epidermal ridges.

#The epidermis consists mainly of a stratified keratinized epithelium populated primarily by keratinocytes, which are keratinizing epidermal cells. See id. The epidermis also harbors a number of other cell populations such as melanocytes, Langerhans cells, Merkel cells, and other cellular migrants. From the dermis outward, the epidermis consists of five layers of keratinocytes known as the stratum basale (stratum germinativum), stratum spinosum, stratum granulosum, stratum lucidum and stratum corneum.

#FIG. 1 depicts a photomicrograph of a human psoriatic biopsy (lower panel) stained for PSMA with murine J591 anti-PSMA antibody. PSMA expression was detected on the dermal vascular endothelium. The arrows indicate the regions showing enhanced PSMA expression in the dermal microvasculature. PSMA expression was also detected in keratinocytes. A control panel (upper panel), without antibody staining, showed only background staining.

#FIGS. 2A–2B depict the amino acid sequence of murine J591 heavy and light chain variable region, respectively. The location of the CDRs is indicated in the Figures; the amino acid numbering is according the Kabat numbering (see, Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91–3242). Note that the CDRs are considered to encompass the Chothia loops and the Kabat hypervariable regions together and the sequences have been annotated accordingly. Heavy Chain: CDR1 is depicted in SEQ ID NO:1; CDR2 is depicted in SEQ ID NO:2; CDR3 is depicted in SEQ ID NO:3; the framework excluding CDR regions is depicted in SEQ ID NO:7; and the framework including CDR regions is depicted in SEQ ID NO:19. Light Chain: CDR1 is depicted in SEQ ID NO:4; CDR2 is depicted in SEQ ID NO:5; CDR3 is depicted in SEQ ID NO:6; the framework excluding CDR regions is depicted in SEQ ID NO:8; and the framework including CDR regions is depicted in SEQ ID NO:20.

#FIGS. 3A–3B depict the amino acid sequence of deimmunized J591 heavy and light chain variable region, respectively. The location of the CDRs is indicated in the Figures; the amino acid numbering is according the Kabat numbering (see, Kabat, E. A., et al. (1991) supra). Note that the CDRs are considered to encompass the Chothia loops and the Kabat hypervariable regions together and the sequences have been annotated accordingly. Heavy Chain: CDR1 is depicted in SEQ ID NO:1; CDR2 is depicted in SEQ ID NO:2; CDR3 is depicted in SEQ ID NO:3; framework 1 is depicted in SEQ ID NO:9; framework 2 is depicted in SEQ ID NO:10; framework 3 is depicted in SEQ ID NO:11; framework 4 is depicted in SEQ ID NO:12; the framework excluding CDR regions is depicted in SEQ ID NO:17; and the framework including CDR regions is depicted in SEQ ID NO:21. Light Chain: CDR1 is depicted in SEQ ID NO:4; CDR2 is depicted in SEQ ID NO:5; CDR3 is depicted in SEQ ID NO:6; framework 1 is depicted in SEQ ID NO:13; framework 2 is depicted in SEQ ID NO:14; framework 3 is depicted in SEQ ID NO:15; framework 4 is depicted in SEQ ID NO:16; the framework excluding CDR regions is depicted in SEQ ID NO:18; and the framework including CDR regions is depicted in SEQ ID NO:22.

#The invention is based, in part, on the discovery that administration to a subject of an antibody to the extracellular domain of prostate specific membrane antigen (PSMA), alone or conjugated to a cytotoxic moiety, reduced the severity of psoriatic lesions (Examples 1–2, and FIGS. 14A–14B). Expression of PSMA protein on hyperproliferative basal and immediately suprabasal keratinocytes, dermal endothelial cells, as well as vascular cells, was detected on the epidermis of a psoriatic lesion from a human subject (Example 3, and FIGS. 1 and 15). The intensity of the staining appears to localize more to less differentiated cells as compared to more differentiated cells. Methods of using the PSMA binding agents to treat, e.g., ablate or kill, PSMA-expressing cells in vitro or in vivo, are encompassed by the invention. Accordingly, in one aspect, the invention provides methods and compositions for treating or preventing skin disorders, e.g., epidermal or dermal disorders, using binding agents, e.g., antibodies or antigen-binding fragments thereof, specific for PSMA.

#In order that the present invention may be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description.

#As used herein, “PSMA” or “prostate-specific membrane antigen” protein refers to mammalian PSMA, preferably human PSMA protein. Human PSMA includes the two protein products, PSMA and PSM′, encoded by the two alternatively spliced mRNA variants (containing about 2,653 and 2,387 nucleotides, respectively) of the PSMA cDNA disclosed in Israeli et al. (1993) Cancer Res. 53:227–230; Su et al. (1995) Cancer Res. 55:1441–1443; U.S. Pat. Nos. 5,538,866, U.S. Pat. No. 5,935,818, and WO 97/35616, the contents of which are hereby incorporated by reference. The long transcript of PSMA encodes a protein product of about 100–120 kDa molecular weight characterized as a type II transmembrane receptor having sequence identity with the transferrin receptor and having NAALADase activity (Carter et al. (1996) Proc. Natl. Acad. Sci. USA 93:749–753). Accordingly, the term “human PSMA” refers to at least two protein products, human PSMA and PSM′, which have or are homologous to (e.g., at least about 85%, 90%, 95% identical to) an amino acid sequence as shown in Israeli et al. (1993) Cancer Res. 53:227–230; Su et al. (1995) Cancer Res. 55:1441–1443; U.S. Pat. No. 5,538,866, U.S. Pat. No. 5,935,818, and WO 97/35616; or which is encoded by (a) a naturally occurring human PSMA nucleic acid sequence (e.g., Israeli et al. (1993) Cancer Res. 53:227–230 or U.S. Pat. No. 5,538,866); (b) a nucleic acid sequence degenerate to a naturally occurring human PSMA sequence; (c) a nucleic acid sequence homologous to (e.g., at least about 85%, 90%, 95% identical to) the naturally occurring human PSMA nucleic acid sequence; or (d) a nucleic acid sequence that hybridizes to one of the foregoing nucleic acid sequences under stringent conditions, e.g., highly stringent conditions.