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Definitions

• TITLE "TREATMENT OF PAPILLOMAVIRUS INFECTIONS" FIELD OF THE INVENTION
• FIELD OF THE INVENTION relates to treatment of papillomavirus infections.
• HPV HPV results in exophytic or flat warts, and infection with some genotypes is also accepted as an antecedent cause of anogenital cancer.
• Current treatment modalities for genital warts are generally destructive and include surgery, cautery, laser surgery, and caustic chemicals as described in, for example, Beutner et al., 1997, Am. J. Med. 102 28-37.
• Warts persist longer and return more frequently in immunosuppressed patients as referred to in Bouwes et al., 1997, Ciin. Dermatol. 15 427-437, suggesting a role for the immune system in the resolution of the lesions.
• a role for local immunity is further supported by the partial therapeutic effectiveness of interferons as referred to in Frazer, I.H. & McMillan, N.A. in Clinical
• VLPs papillomavirus virus-like particles
• U.S. Patent No. 5437951 also makes it clear that prophylactic vaccination can be useful for productive PV lesions which usually express L1 and L2 capsid proteins. Such lesions may occur in benign infections such as warts of laryngeal papillomatosis.
• This reference also establishes that protective immunity against both benign and malignant PV disease can be induced by administration of an effective amount of recombinant L1 capsid protein to an individual at risk for PV infections.
• a vaccine comprising the capsid protein can be directly administered either parentally or locally according to conventional immunization protocols.
• HPV16 E7 VLPs into mice protected the mice from tumour challenge even in the absence of adjuvant.
• HPV16L1/L2 VLPs were not effective in this regard, a not unexpected result since the tumor was and
• hybrid or chimeric VLPs formed from HPV L1 which also incorporated a single HPV16 E7 cytotoxic T lymphocyte (CTL) epitope and a single HIV gp 160 CTL epitope induced a strong CTL response upon immunization.
• CTL cytotoxic T lymphocyte
• the invention provides a method of treating an existing PV infection which includes the step of administration of PV VLPs selected from the group consisting of PV L1 VLPs and PV L1/L2 VLPs to a patient suffering from the PV infection.
• the method of the invention is especially applicable to existing genital warts which are caused by HPV types 6, 11 , 34, 39, 41-44 and 51-55.
• the warts that may be especially relevant for treatment are caused by HPV6 and HPV11.
• the PV infections are epithelial lesions and more preferably such lesions are selected from the group consisting of palmar warts, planter warts, ano-genital warts, flat and planar warts of the skin and muscosal surfaces, CIN, equine sarcoid or replicating or vegetative
• an existing patient may be checked for the cause of his or her infection and, in this regard, a biopsy may be taken for PV typing.
• the PV typing is effected by antibody-based or nucleic acid-based techniques which are well known to those skilled in the art.
• the PV-typing is effected by nucleic acid amplification techniques such as PCR.
• VLPs may be produced by standard methods well known in the art which, for example, are reported in Qi et al., 1996, Virology 216 35-45. Such standard methods are also described in International Publication No. WO93/02184, Australian Patent No. 683220, Yamada et al., Dec. 1995, J. Virol. 7743-7753, U.S. Patent No. 5437951 , U.S. Patent No. 5744142, Rose et al., 1993, supra, Kirnbauer er a/., 1993, J. Virol. 67(12) 6929-6936, Sasegawa et al., 1995, Virology 206 126-135 and Schiller and Roden, 1995, Papillomavirus Report 6(5) 121-128.
• VLPs can be produced by a wide variety of methods which basically include cloning the L1 (or L1 and L2) gene into a suitable vector and expressing the corresponding conformational coding sequences for these proteins in a eukaryotic cell transformed by the vector. Subsequently all of the capsid protein coding sequence should be expressed and thus substantially all of the capsid coding sequence is cloned. Insect cells are preferred host cells although yeast cells may also be utilized if required. Similarly, other eukaryotic and prokaryotic systems may be used to express L1 or L1 and L2 proteins provided the expressed proteins self-assemble into VLPs.
• baculovirus expression system is used wherein the L1 or L1 and L2 genes are inserted into a baculovirus expression vector containing flanking baculovirus sequences to form a gene construct and the recombinant DNA is co-transfected with wild-type baculovirus DNA into Sf-9 insect cells.
• PV VLPs may be dissolved in any suitable physiological vehicle inclusive of saline, water, PBS
• PV VLPs phosphate buffered saline
• Dosages may be 3-6 times over a period of 8-16 weeks or more preferably 2-4 weeks.
• immunization with HPV6 and more particularly HPV6b VLPs give immune responses cross reactive with HPV11 but not HPV16. Therefore, immunization with HPV6 VLPS may provide protection against HPV11 infections and vice versa, i.e. immunization with HPV11 VLPs may give protection against HPV6 infections.
• immunization protocols similar concentrations or dosages of VLPs as described above may be adopted and use of any physiological vehicle may be utilized.
• parenteral administration and, in particular, intramuscular administration, is preferred.
• VLPs were produced under good laboratory practice conditions using an HPV6bL1 recombinant baculovirus (L1rBV) previously described in Qi et al., 1996, Virology 216 35-45.
• Cultures of SF9 cells in SF900-II medium (Sigma) were infected with L1 rBV at an MOI of 10. After 48 hours, cultures were harvested, and the cell pellets pooled, assayed for L1 by immunoblot and for VLPs by electron microscopy, and frozen at -80° until further use.
• Thawed cell pellets were further purified by discontinuous sucrose gradient centrifugation, and by continuous Cesium Chloride gradient centrifugation, and assayed for VLP content, as previously described in Qi et al., 1996, supra and Park et al., 1993, J. Virol. Methods 45 303-318.
• Material of density 1.26-1.30 g/cm 3 which was >80% HPV6bL1 protein by gel analysis, and contained substantially complete virus particles on EM (VLPs), was then subjected to exhaustive dialysis against phosphate buffered 0.9% NaCI with Calcium and Magnesium(PBS), and aliquoted at 50 ⁇ g protein/100 ⁇ l in glass vials.
• a cohort of five patients receiving 10 ⁇ g VLPs were tested for routine haematology (FBE, Differential White Count), and biochemistry (AST, ALT, Bilirubin, Alkaline Phosphatase, Total Protein, Albumin, Globulins, Glucose, Urea, Creatinine, Uric Acid) tests prior to, and three days, 1 , 2, 4, 8, and 12 weeks after the first immunization.
• Samples from subjects were tested by 12 channel automated chemistry analyzer (Beckmann CX4) and 6 channel Coulter haematology (Coulter T-540) analyzer.
• Serum was collected prior to entry and every two weeks throughout the study, for assay for VLP specific antibody by ELISA.
• ELISA plates (Flow Laboratories) were coated with HPV6b, HPV11 or HPV16 VLPs (10 ⁇ g/ml) in PBS buffer, held overnight, and blocked with defatted skim milk.
• Test and control sera were added at 1 :100 dilution and binding detected by HRP-conjugated anti-human IgG (Sigma) or HRP-conjugated anti-human IgG, A, M (Silenius). Mean reactivity of each serum with defatted skim milk, which ranged from 0.001 to 0.113 (mean 0.032) was in each case subtracted.
• the complete set of sera was tested within a single assay and three independent assays of the serum set were carried out with highly correlated results (r 2 > 0.95). DTH testing
• VLP vaccine material was used as an antigen for DTH testing.
• DTH testing was carried out for 32 subjects after the primary three dose immunization and antibody testing protocol was complete at week 10-12.
• 20 ⁇ l (10 ⁇ g) of VLP suspension was delivered intradermally on the volar aspect of the forearm.
• Biopsies were scored visually at 48 hours as 0 (no induration), 1 (1-3 mm duration), 2 (4-10 mm induration) and 3 (>10 mm induration).
• DTH sites were biopsied using, a 3 mm punch biopsy under 1 % Lignocaine local anaesthesia.
• Biopsies were fixed in neutral buffered formalin, and processed for routine H+E sections and for immunohistochemistry as previously described in Pettit e/ a/., 1997, J. Immunol. 159 3681-3691. Immunohistochemistry
• mice were incubated at room temperature in wet-chamber with primary antibodies; mouse anti-human CD1a (Immunotech-Coulter, clone BL-6 pre-diluted), rabbit anti-human CD3 (1 :250) and mouse anti-human CD8 (clone C8/144B), CD68 (clone PG-M1 ), HLA-DR (clone TAL-1B5) and CD20 (clone L26) (DAKO, Denmark) all in 1 :50 dilutions for 60 minutes.
• mouse anti-human CD1a Immunotech-Coulter, clone BL-6 pre-diluted
• rabbit anti-human CD3 (1 :250
• mouse anti-human CD8 clone C8/144B
• CD68 clone PG-M1
• HLA-DR clone TAL-1B5
• CD20 clone L26
• Sections were treated with biotinylated rabbit anti-mouse or swine anti- rabbit (1 :200) secondary antibody and with streptavidin conjugated horseradish peroxidase (DAKO, Denmark) (1:300). For double immunostaining, the sections were further treated with second primary antibody followed by its corresponding biotinylated second secondary antibody. Streptavidin ABC/alkaline phosphatase conjugate (DAKO, Denmark) was used to tag the second antibody. The first and second antibodies were subsequently demonstrated by developing with substrate chromogen kits using DAB (brown) and Fast-red (red) (DAKO, Denmark). Sections were counterstained using Myer's haematoxylin. Statistical analysis Univariate and multivariate analysis was carried out using
• VLP specific DTH was measured using a single intradermal injection of VLPs at various times after the second or third immunization. DTH was not tested prior to initiating immunization, primarily to avoid a immunising effect of the DTH skin test. The majority of patients, regardless of dose of VLPs or time after immunization, had a 2+ to 3+ clinical DTH response, and all patients had some visible response. For 28 subjects, DTH reactions were biopsied using a 3 mm skin punch, and subjected to histologic analysis including, for five biopsies, detailed immunohistochemical assessment. Typical DTH reaction including lymphoid and monocytic infiltrate was observed round vessels and subcutaneously (FIG. 1 ).
• Infiltrates for the five biopsies so assessed included CD1a+ve Langerhans cells, CD4 and CD8+ve T cells, and DR+ve macrophages.
• a five point scale was used for assessing DTH reactions histologically, according to the extent of the inflammatory infiltrate round blood vessels and subcutaneously, the number of involved vessels, and the presence of non-lymphoid inflammatory cells including eosinophils. The majority of the biopsies scored highly, and the DTH score was independent of VLP dose or number of immunizations.
• CD1 a+ Langerhans cells were seen in the epidermis, and rarely in the dermis, and some CD1 a+ve cells co- expressed HLA-DR.
• the perivascular mononuclear inflammatory infiltrate was predominantly of CD3+ T-cells, with CD68+ macrophages and a few CD20+ B cells.
• CD3+ T-cells Approximately 8-10% of the CD3+ T-cells were CD8+.
• Numerous HLA-DR+/CD3+ activated T-cells and some CD68+/DR+ macrophages were demonstrable in the dermis and in deeper tissue.
• the number of warts at entry to the study ranged from 1 to 15, and resolution of warts during the period of observation was more common amongst those with fewer warts (Table 2).
• Wart area at entry ranged from 25 to 950 mm 2 .
• Mean wart area at entry amongst those subjects not clearing their warts during the study was 520 mm +/- 120, whereas mean area amongst those clearing their warts was 260 mm +/- 47 mm.
• PV viral capsid proteins including L1 are expressed in warts. Although detectable L1 protein is limited to the more super icial layers of the epidermis in warts, possibly as a consequence of L1 mRNA instability as described in Sokolowski et al., 1998, J. Virol. 72 1504-1515, cells expressing undetectably small amounts of L1 are nevertheless susceptible to L1 specific T cell mediated lysis as described in De Bruijn et al., 1998, Virology 250 371-376.
• VLP immunotherapy may alter the outcome of human genital warts by induction of PV protein specific CTL which lyse the replicating HPV infected parabasal keratinocytes which allow wart persistence.
• CTL cytotoxic T lymphocytes
• Naturally occurring papillomavirus infection is poorly immunogenic, presumably because the virus causes cell proliferation without local immunization, and infects only the superficial layer of the skin as shown in Frazer, I.H., 1996, Curr. Opin. Immunol. 8 484-491.
• specific immunotherapy for PV infection with VLPs in man might be expected to give a better clinical outcome than the immune response induced by infection, as is apparently demonstrated in the current study.
• Papillomavirus infection should therefore be a good candidate for studies of efficacy of newer vaccine delivery systems designed to produce effective cell mediated immunotherapy in man.
• induction of cell mediated immunity to HPV proteins would be a desirable feature in an HPV prophylactic vaccine, to eliminate any cells infected with HPV that escaped neutralization by VLP specific antibody.
• Demonstration of DTH to VLPs in subjects with genital warts in the present study is in keeping with the ability of VLPs administered without adjuvant to mice to induce cell mediated immune responses including specific CTL as described in Greenstone ef al., 1998, supra, Peng et al., 1998, supra and Dupuy ef al.., 1997, Microb. Pathog. 22 219-225.
• VLPs A significant increase in VLP specific antibody titre was observed in the current study in the majority of non-immune subjects after three immunizations and in partially immune subjects after one immunization.
• administration of VLPs to patients with HPV infection apparently induces immunity to the same epitopes as are immunogenic in the course of natural infection.
• Even 1 ⁇ g or less of VLPs are highly immunogenic in mice, rabbits, dogs and cattle, whether given with or without adjuvant as described in Breitburd et al., 1995, supra, Kirnbauer ef al., 1996, supra and Ch stensen ef al., 1994, J. Virol. 70 960-965.
• Murine Langerhans cells can express 6 ⁇ 1 integrin as described in Price ef al.., 1997, J. Exp. Med. 186 1725-1735, recently described as a candidate receptor molecule for papillomavirus as described in Evander ef al., 1997, J. Virol. 71 2449-2456, suggesting that direct uptake of PV VLPs by LC may explain their unadjuvanted immunogenicity.
• HPV6b VLPs produced humoral immune responses cross reactive with HPV11 , but not with HPV16, confirming that VLP immunization induces antibody with cross reactivity between closely related PV types and a lack of cross reactivity between more distant types, as has been described following natural infection as described in Bernard ef al.., 1994, Curr. Top. Microbiol. Immunol. 186 33-54, Ch stensen ef al., 1994, Virology 205 329-355 and Rose ef al., 1994, J. Gen. Virol. 75 2445-2449 and Christensen ef al., 1994, Virology 205 329- 355. This observation is of significance for papillomavirus prophylactic vaccines.
• HPVL1 VLPs are a good candidate for therapeutic vaccines against HPV infection.
• VLPs may include chimeric VLPs which comprise a protein E component.
• a method of treatment of an existing PV infection which includes the step of administration of PV VLPs in the presence of adjuvant to a patient suffering from the PV infection.
• the adjuvant is preferably one that induces cellular responses and may be included from the group consisting of (1 ) lipid A and derivatives, (2) Quillaia saponins and derivatives, (3) mycobacteria and components or derivatives therefrom (4) IL 12, GMCSF and other Th1 inducting cytokines and (5) oxidized mannan and analogues therof.
• FIG. 1 A first figure.
• Antibody to HPV6b (A) and HPV16L1 (B) capsid protein was measured at a serum dilution of 1:100 by ELISA assay using VLPs prepared with recombinant baculovirus. Results from subjects immediately prior to immunization [hatched] and at week 20 [solid], are shown.
• HPV1 HPV1 . Sera from prior to immunization are shown as circles and from week 20 as squares.

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