WO2013092875A1

WO2013092875A1 - Vaccines against hpv

Info

Publication number: WO2013092875A1
Application number: PCT/EP2012/076404
Authority: WO
Inventors: Ole Henrik Brekke; Agnete Brunsvik Fredriksen; Ali AREFFARD; Mona Mari LINDEBERG
Original assignee: Vaccibody As
Priority date: 2011-12-21
Filing date: 2012-12-20
Publication date: 2013-06-27
Also published as: DK2793937T3; RU2014129788A; KR102057265B1; JP6258864B2; EP2793937A1; NZ626124A; ES2730718T3; CN104039833A; KR20140107569A; CA2858963A1; BR112014015016A8; CA2858963C; EP3533462A1; IL233217B; US9901635B2; AU2012356969B2; AU2012356969A1; PT2793937T; RU2644201C2; TR201908199T4

Abstract

The present invention relates to therapeutic compounds, such as vaccines against human papillomavirus (HPV) and in particular to DNA vaccines against HPV16 or HPV18. The invention further relates to protein construct encoding homodimeric peptides, which peptides may be released from a DNA vaccine or used separately. Further described are pharmaceutical formulations, host cells and methods for producing the vaccines, as well as methods for the treatment of various HPV induced diseases, such as cancers and infectious diseases by application.

Description

VACCIN ES AGAINST H PV FIELD OF TH E INVENTION

The present invention relates to therapeutic compounds, such as vaccines against human papillomavirus (HPV) and in particu lar to DNA vaccines against H PV16 and/or H PV18. The invention further relates to protein construct encoding homod imeric peptides, which peptides may be released from a DNA vaccine or used separately. Further described are

pharmaceutical formu lations, host cells and methods for producing the vaccines, as well as methods for the treatment of various H PV induced d iseases, such as cancers and infectious d iseases by application. BACKGROUN D OF THE INVENTION

It is now well established that human papillomavirus (HPV) is the cause of cervical cancer and other H PV-associated malignancies such as anogenital (anus, vulvar, vag inal and penile) cancers and a subset of head and neck cancers. In particu lar, H PV16 and H PV 18 are responsible for about 70% of all cervical cancers worldwide. To date, two prophylactic HPV vaccines are on the market (Gardasil and Cervarix) . The aim of the prophylactic vaccines is to induce humoral immune responses by stimulating the production of neutralizing antibod ies specific for the HPV viral ca psid proteins, LI and L2. Although the preventive vaccines are an important milestone for the control of H PV induced cervical cancer and possibly other H PV-associated malignancies, the effect of these vaccines will not be sig nificantly observed for 20-40 years (Ma B et al., Current Cancer Therapy Reviews, 2010) . Moreover, since the coverage of mass vaccination for the prophylactic vaccines are to date limited in add ition to a substantial population worldwide that already are H PV infected, HPV-associated malig nancies will continue to prog ress. Thus, it will be important to develop HPV-specific therapeutic vaccines in order to reduce the mortality and morbid ity of H PV-associated malignancies and its precursor lesions (Ma B et al., Current Cancer Thera py Reviews, 2010) .

The development of various cancer vaccines and cancer immunotherapy strateg ies has throughout the last two decades expanded . Still, only one thera peutic cancer vaccine, called Provenge (Dendreon INC) has so far been approved to be applied as standard therapy for prostate cancer. Notably, due to ethical reasons the majority of therapeutic cancer vaccines are tested on a patient group bearing a late stage tumor. This patient g roup is substantially immunosu ppressed meaning that the tumor cells have for long escaped the immune system and contributed to induce immunolog ical tolerance to the tumor along carcinogenesis. In add ition, the choice of antigens (tumor-specific vs. tumor-associated) applied as vaccines are critical in order to induce tumor-specific immune responses and avoid killing of healthy cells in the patients which may lead to serious adverse events. Thus, the major challenges in cancer immunotherapy are to break the immunological tolerance and activate tumor-specific effector functions to recog nize and kill tumor cells. Althoug h some case reports show clinical response to therapeutic cancer vaccines in late stage tumor patients, the most common primary end point is to observe the impact on overall survival compared to conventional therapy (surgery, chemo and rad iation therapy) . However, most studies are either not conclusive or that they completely fail to show this. One reason for the negative results lies in the patient g roup carrying end-stage tumors that are challeng ing to treat in the first place. A possible strategy cou ld be to include patients with early-stage tumors in therapeutic vaccine trials.

One strategy is to target pre-cancerous lesions. The challenges for this strategy are mainly the lack of reliable biomarkers that are specifically expressed by precancerous lesions for many tissues and poor med ical screening (either non-existing or that the existing method suffers from lack of sensitivity) . Exceptionally, this is not the case for H PV-induced malignancies. For instance, the majority of western countries have good screening programs for cervical dysplasia and cervical cancer by performing the Papanicolaou test (Pap smear test) . If there are unclear or abnormal results from Pap smear test, colposcopy will be performed (National Cervical Cancer Coalition) . HPV-testing may also be recommended for some patients to detect the presence of "hig h-risk" HPV-type in the precancerous lesion. Thus, HPV represents a potential biomarker for HPV-associated precancerous lesions, in particu lar cervical intraepithelial dysplasia (CIN). DNA vaccines have shown increasing promise for the treatment of human d iseases, in particu lar cancer. DNA vaccines induce strong antigen-specific immune responses and can be repeatedly administered to maintain the target-specific immune responses. Such vaccines are considered to be safe and simple and cheap to produce on a large scale compared to other cancer therapeutic formats. Numerous immunotherapeutic interventions fail to induce immunolog ical memory. Exceptionally, DNA vaccination ensures sustained release of the vaccine product in vivo which enhances antigen-specific immunolog ical memory. Direct delivery of antigens to professional antigen-presenting cells (APCs) stimulates both CD4+ and CD8+ T cell immune responses in vivo. Such strong cellu lar immune responses have been demonstrated to specifically recognize and kill antigen-positive malignant cells efficiently both in vitro and in vivo. There is still a need in the art for improved vaccines for inducing strong and specific immune responses against HPV responsible for both infectious d iseases and cancers.

OBJECT OF TH E INVENTION

It is an object of embod iments of the invention to provide specific and highly effective therapeutic compounds, such as DNA vaccines against d iseases and cond itions caused by H PV.

SUM MARY OF TH E INVENTION

It has been found by the present inventors that by combining the antigens of the early gene products E6 and E7 from HPV, such as from H PV16 and/or H PV18 with the targeting module of hMIP-la, therapeutic vaccines are provided, wherein the strong immu nogenic epitopes of H PV gene products are presented with high efficiency to APCs to induce a specific and strong immune response. The products accord ing to the present invention is primarily envisioned as therapeutic nucleic acid vaccines, such as DNA vaccines, wherein a nucleic acid construct encod ing the vaccibody construct is used as the therapeutic compound lead ing to in vivo production of the protein product within the person receiving the vaccine. However, as an alternative the protein product itself may be formulated and used directly in the vaccine.

Accord ing ly, in a first aspect the present invention relates to a homod imeric protein of two identical amino acid chains, each amino acid chain comprising ( 1) a signal peptide, (2) a targeting unit, (3) a dimerization motif, and (4) an antigenic unit, said targeting unit comprising an amino acid sequence having at least 80 % sequence identity to the amino acid sequence 24-93 of SEQ ID NO : l, and an antigenic unit comprising an amino acid sequence of human papillomavirus (HPV), such as an antigenic unit comprising an amino acid sequence of H PV16 and/or H PV18, such as an antigenic unit derived from early proteins E6 and/or E7 of H PV16 and/or H PV18. In a second aspect the present invention relates to an amino acid chain comprising (1) a sig nal peptide, (2) a targeting unit, (3) a d imerization motif, and (4) an antigenic unit, said targeting unit comprising an amino acid sequence having at least 80 % sequence identity to the amino acid sequence 24-93 of SEQ ID NO : l, and an antigenic unit comprising an amino acid sequence of human papillomavirus (HPV), such as an antigenic u nit comprising an amino acid sequence of HPV16 and/or H PV18, such as an antigenic unit derived from early proteins E6 and/or E7 of HPV16 and/or H PV18, which amino acid chain is able to form a homodimeric protein accord ing to the invention. In a third aspect the present invention relates to a nucleic acid molecu le, such as a DNA, encod ing an amino acid chain comprising (1) a sig nal peptide, (2) a targeting unit, (3) a d imerization motif, and (4) an antigenic unit, said targeting unit comprising an amino acid sequence having at least 80 % sequence identity to the amino acid sequence 24-93 of SEQ ID NO : l, and an antigenic unit comprising an amino acid sequence of human papillomavirus (H PV), such as an antigenic unit comprising an amino acid sequence of H PV16 and/or H PV18, such as an antigenic unit derived from early proteins E6 and/or E7 of H PV16 and/or HPV18, which amino acid chain is able to form a homod imeric protein accord ing to the invention.

In a further aspect the present invention relates to a homodimeric protein according to the invention, or an amino acid chain accord ing to the invention, or the nucleic acid molecule accord ing to the invention for use as a med icament.

In a further aspect the present invention relates to a pharmaceutical composition comprising a homod imeric protein accord ing to the invention, or an amino acid chain accord ing to the invention, or the nucleic acid molecu le accord ing to the invention.

In a further aspect the present invention relates to a host cell comprising the nucleic acid molecu le accord ing to the invention.

In a further aspect the present invention relates to a method for preparing a homod imeric protein accord ing to the invention, or an amino acid chain of the invention, the method comprising a) transfecting the nucleic acid molecu le accord ing to the invention into a cell popu lation; b) cu lturing the cell population; c) collecting and purifying the homod imeric protein, or am ino acid chain expressed from the cell population.

In a further aspect the present invention relates to a method for preparing a vaccine, such as a DNA vaccine, comprising an immu nologically effective amount of a nucleic acid molecule accord ing to the invention, the method comprising a) preparing a nucleic acid molecu le accord ing to the invention; b) dissolving the nucleic acid molecule obtained under step a) in a pharmaceutically acceptable carrier, d iluent, or buffer.

In a further aspect the present invention relates to a vaccine against HPV comprising an immunolog ically effective amount of a homod imeric protein accord ing to the invention, or an amino acid chain according to the invention, or nucleic acid molecu le, such as a DNA, accord ing to the invention, wherein said vaccine is able to trigger both a T-cell- and B-cell immune response. In a further aspect the present invention relates to a method of treating or preventing a H PV induced d isease or cond ition, such as a cancer or an infectious d isease caused by HPV in a patient, the method comprising administering to the patient in need thereof, a homodimeric protein accord ing to the invention, or an amino acid chain accord ing to the invention, or the nucleic acid molecule, such as a DNA, accord ing to the invention.

LEGENDS TO THE FIGURE

Figure 1 : The overall structure of vaccibody vaccines with E7/E6 fusion antigen. Shown are both DNA and protein formats. The vaccibody consist of three functional modules; the chemokine human ΜΙΡ-Ια (Ι_ϋ78β) in the targeting module, hinge and CH3 sequences from human IgG3 in the d imerization modu le and fu ll-length E7 and/or E6 fusion in the vaccine module.

Figure 2 : The suggested mode of action for a Vaccibody DNA vaccine against H PV -induced malignancies. Naked DNA plasmid encod ing vaccibody is injected intradermal followed by electroporation. The plasmid is taken up by local cells and vaccibody proteins are produced and secreted . The chemotactic targeting modu les attract CCRl and CCR5 expressing antigen presenting cells (APC) and ensure bind ing and u ptake into dend ritic cells (DC) . The DC will present antigenic peptides to CD4+ and CD8+ T cells and the CD8+ T cells will kill H PV infected and transformed cells in the cervix.

Figure 3 : ELISPOT results showing the number of E7 and E6 specific T cell responses as a function of d ifferent amounts of vaccine administered . C57BL/6 mice were injected i.d . with naked DNA plasmids encod ing VB1009 and VB1016 and their correspond ing controls followed by electroporation (Cellectis, France) on day 0 and day 7. Splenocytes were harvested at day 21 and stimu lated with M HC class I-restricted E7 or E6 peptide for 24h. The number of IFNy secreting splenocytes was calculated by ELISPOT. (A)E7-specific responses after i.d .

vaccination with 25pg of VB1009, control 1 (antigen alone) and pUMVC4a (empty vector) . (B) E7-specific responses after i.d . vaccination with 12.5 and 1.4pg of VB1016, control 2 (antigen alone) and pUMVC4a (empty vector) . (C) E6-specific responses after i.d . vaccination with 12.5 and 1.4pg of VB1016, control 2 (antigen alone) and pUMVC4a (empty vector) .

Figure 4. Therapeutic effect of VB1016 shown by measured tumor volume. C57BL/6 mice were injected s.c. with 5xl0⁵ TC-1 cells at day 0. At day 3 and day 10, the mice were injected i.d . with 12.5pg naked DNA plasmids encod ing VB1016, control 2 or empty vector followed by electroporation (Cellectis, France) . The tumor sizes were measured by caliper two to three times a week and tumor volume calculated . Figure 5. Therapeutic effect of VB1016 shown by measured tumor volume. C57BL/6 mice were injected s.c. in the neck area with 5xl0⁴ TC-1 cells at day 0. At day 3,7 and day 10, the mice were injected i.d . with 20pg or 2pg naked DNA plasmids encod ing VB1016, control 2 or empty vector followed by electroporation (Cellectis, France) . The tumor sizes were measured by caliper two to three times a week and tumor volume calculated .

Figure 6.Therapeutic effect of VB1020 and VB1021 shown by measu red tumor volume. C57BL/6 mice were injected s.c. in the thig h with 5xl0⁴ TC-1 cells at day 0. At day 3 and day 10, the mice were injected i.d . with 10pg naked DNA plasmids encod ing VB1016, VB1020, VB1021 or empty vector followed by electroporation (Cellectis, France) . The tumor sizes were measured by caliper two to three times a week and tumor volume calculated .

DETAILED DISCLOSURE OF TH E INVENTION

The constructs and DNA vaccine technology described herein by the inventors of the present invention (also referred to as "vaccibody" molecules/vaccines/constructs) represents a novel vaccine strategy to induce strong and specific immune responses for both infectious d iseases and cancer. The HPV E6/E7, such as HPV16 or H PV18 E6/E7 vaccine described herein may be administered as a DNA vaccine by intradermal injection, preferably followed by

electroporation. This resu lts in the uptake of the DNA-construct encod ing the vaccibody- H PV16 and/or H PV18 E6/E7 vaccine in cells at the site of injection (dermis) includ ing dend ritic cells (Langerhans cells), lead ing to in vivo production of the vaccibody-E6/E7 molecu le.

The early gene products E6 and E7 from "high-risk" H PV types such as HPV16 and 18 may be responsible for transformation of the basal-epithelium cells and induction of precancerous lesions. Both proteins consist of hig hly immunogenic epitopes and are shown herein to induce strong immune responses lead ing to specific erad ication of "hig h-risk" HPV positive tumor cells both in vitro and in vivo.

The vaccibody molecu le described herein is a homod imer consisting of three modules;

targeting module, dimerization module and the vaccine modu le (Figure 1) . Genes encod ing the three modules are genetically eng ineered to be expressed as one gene. When expressed in vivo, the vaccibody molecule targets antigen presenting cells (APCs) which results in an enhanced vaccine potency compared to identical, non-targeted antigens. In vivo expression of the chemokine human macrophage inflammatory protein 1 alpha (hMIP-la/ Ι_ϋ78β) leads to attraction of DCs, neutrophils and other immune cells carrying the CCR1 and CCR5 receptors to the site of expression. Thus, the vaccibody molecule consisting of hMIP-la as the targeting module, will not only target the antigens to specific cells, but in add ition g ive a response- amplifying effect (adjuvant effect) by recruiting specific immune cells to the injection site. This unique mechanism may be of g reat importance in a clinical setting where patients can receive the vaccine without any add itional adjuvants since the vaccine itself g ives the adjuvant effect. The inventors of the present invention describes herein vaccine constructs where the antigenic module consist of the E7 full length genetic sequence in fusion to the E6 full length sequence orig inating from the HPV16 or H PV18 subtype. The advantage of this format is that both E6 and E7 will be present in one construct and may thus be equally expressed in vivo. Consequently, one vaccibody molecule consisting of a multi-antigenic unit may represent equal levels of E6 and E7 for the immune system. The HPV16 E6 and E7 gene products are oncogenic in their natural form. To neutralize their oncogenic properties, mutations at specific sites may be introduced in the E6 and E7 genetic sequence.

The mutations, includ ing deletions, may be introduced at specific sites, known to inhibit the oncogenic properties of E6 and E7, such as any one described in any of Dalai S et al., J Virol, 1996; Munger K et al., EM BO, 1989; Nakagawa S et al., Virology, 1995; Crook T et al., Cell, 1991; Munger K et al., HPV Compendium Online, 1997

(http://www.stdgen.lanl.gOv/COMPENDIUM_PDF/97PDF/3/E7.pdf); Nguyen, M et al., J Virol, 2002; Nomine Y et a., Molecular Cell, 2006; Moody C et al., Nat Rev Cancer, 2010, Polakova I et al., Vaccine, 2010; Xie Q, Virologica Sinica, 2011; Mesplede T et al., J Virol, 2012; US 2008/0102084 and US6306397, which references are hereby incorporated by reference. Accord ing ly, in some aspects of the invention, the constructs accord ing to the present invention contain H PV16 E6, E7 or HPV16 E6/E7 chimeric constructs with one or more mutations in either of HPV16 E6, E7 or both at a position known to inhibit the oncogenic properties as described in Dalai S et al., J Virol, 1996; Mu nger K et al., EMBO, 1989;

Nakagawa S et al., Virology, 1995; Crook T et al., Cell, 1991 ; Munger K et al., HPV

Compend ium Online, 1997

(http ://www.stdgen. lanl.gOv/COMPEN DIUM_PDF/97PDF/3/E7. pdf) ; Nguyen, M et al., J Virol, 2002; Nomine Y et a., Molecular Cell, 2006; Moody C et al., Nat Rev Cancer, 2010, Polakova I et al., Vaccine, 2010; Xie Q, Virologica Sinica, 2011; Mesplede T et al., J Virol, 2012; US 2008/0102084 or US6306397. In other aspects of the invention, the constructs accord ing to the present invention contain HPV18 E6, E7 or H PV18 E6/E7 chimeric constructs with one or more mutations in either of HPV18 E6, E7 or both at a position known to inhibit the oncogenic properties as described in Dalai S et al., J Virol, 1996; Munger K et al., EM BO, 1989; Nakagawa S et al., Virology, 1995; Crook T et al., Cell, 1991 ; Munger K et al., H PV Compend ium Online, 1997

(http ://www.stdgen. lanl.gOv/COMPEN DIUM_PDF/97PDF/3/E7. pdf) ; Moody C et al., Nat Rev Cancer, 2010, US 2008/0102084 and US6306397. There is a possibility that the vaccibody-moiety (targeting and d imerization modules) may erad icate the oncogenic properties of E6 and E7 wildtype proteins in the final fusion protein. Thus, in yet another aspect of the invention is the utilization of the wildtype full-length E6 and/or E7 sequences in the vaccibody construction.

The invention describes several variant of Vaccibody H PV therapeutic DNA vaccines all based on the overall format described in figure 1, the therapeutic vaccibody-H PV DNA vaccines encodes genes that are naturally expressed in humans; the targeting module genes encode the chemokine hMIP-la, which binds to its cog nate receptors, CCR1 and CCR5 expressed on the cell surface of APCs. The dimerization module genes may encode hinge regions and constant heavy chain 3, such as from human IgG3 which connects two vaccibody monomers generating a homod imer molecu le. Genes encod ing the vaccine module for the current strategy consist of HPV, such as H PV16 and/or HPV18 E7 and E6 antigens, such as the full length HPV16 E7 and E6 antigens, optionally comprising one or more mutation to inhibit the oncogenic properties. Once administered in vivo by i.d . injection followed by electroporation, dermal cells taking up the vaccine construct will express the vaccibody-HPV molecule. The in vivo produced vaccibody vaccines target to CCR1 and CCR5 expressed on the surface of APCs in the skin, in particular DCs. The bind ing of the vaccibody molecule to its cog nate receptors leads to internalization of the complex in the APC, deg radation of the proteins into small peptides that are loaded onto M HC molecu les and presented to CD4⁺ and CD8⁺ T cells to induce HPV16 E6 and E7 specific immune responses. Once stimu lated and with help from activated CD4⁺ T cells, CD8⁺ T cells will target and kill HPV16 E6 and E7 expressing cells (Figure 2) . Such enhanced immune responses to a vaccine with a "bu ilt-in" adjuvant effect may potentially overcome tumor-escape (tumor immune surveillance) by breaking

immunolog ical tolerance and efficiently kill malig nant cells. The hMIP-la targeting unit may be connected through a d imerization motif, such as a hinge reg ion, to an antigenic unit, wherein the later is in either the COOH-terminal or the N H2-terminal end . The present invention not only relates to a DNA sequence cod ing for this recombinant protein, but also to expression vectors comprising these DNA sequences, cell lines comprising said expression vectors, to treatment of mammals preferentially by immunization by means of Vaccibody DNA, Vaccibody RNA, or Vaccibody protein, and finally to pharmaceuticals and a kit comprising the said molecules.

The d imerization motif in the proteins accord ing to the present invention may be constructed to include a hinge reg ion and an immunoglobulin domain (e.g . Cy3 domain), e.g .

carboxyterminal C domain (C_H3 domain), or a sequence that is substantially identical to said C domain. The hinge reg ion may be Ig derived and contributes to the d imerization through the formation of an interchain covalent bond (s), e.g . disu lfide bridge(s) . In add ition, it functions as a flexible spacer between the domains allowing the two targeting units to bind simu ltaneously to two target molecu les on APC expressed with variable distances. The immunoglobulin domains contribute to homod imerization throug h non-covalent interactions, e.g . hyd rophobic interactions. In a preferred embod iment the C_H3 domain is derived from IgG . These d imerization motifs may be exchanged with other multimerization moieties (e.g . from other Ig isotypes/subclasses) . Preferably the dimerization motif is derived from native human proteins, such as human IgG.

It is to be understood that the d imerization motif may have any orientation with respect to antigenic unit and targeting unit. In one embod iment the antigenic unit is in the COOH- terminal end of the d imerization motif with the targeting unit in the N-terminal end of the d imerization motif. In another embod iment the antigenic unit is in the N-terminal end of the d imerization motif with the targeting unit in the COOH-terminal end of the d imerization motif.

International application WO 2004/076489, which is hereby incorporated by reference d iscloses nucleic acid sequences and vectors, which may be used accord ing to the present invention.

The proteins according to the present invention include an antigenic unit derived from HPV, such as HPV16 E7 and E6 antigens, such as the full length HPV16 E7 and E6 antigens, as well as immunogenic fragments or variants thereof. The antigenic sequence shou ld be of sufficient length. The minimal length of such antigenic unit may be around 9 amino acids. According ly in some embod iments, the antigenic unit derived from H PV comprises an amino acid sequence of at least 9 amino acids corresponding to at least about 27 nucleotides in a nucleic acids sequence encod ing such antigenic unit. Preferably the antigenic u nit derived from H PV is considerably longer, such as the full length H PV16 E7 and E6 antigens. Diversity arises within a g iven HPV genotype throug h limited nucleotide changes in the cod ing (at a frequency of < 2%) and non-cod ing (at a frequency of < 5%) regions (Bernard, HU et al., Int J Cancer, 2006) . Such variants phylogenetically segregate based on their geographical orig in and are therefore labeled European, African, Asian, Asian-American and North American. Insertion of such sequences in a Vaccibody format mig ht lead to activation of both arms of the immune response.

Immunization by means of Vaccibody protein, Vaccibody DNA, or Vaccibody RNA, the latter two executed e.g . by intramuscu lar or intradermal injection with or without a following electroporation, are all feasible methods accord ing to the present invention.

As discussed above, the present invention relates to a vaccine composition against cancer or infectious d iseases caused by H PV, the vaccine composition comprising an immunolog ically effective amount of the nucleic acid encod ing the molecu le of the invention or degenerate variants thereof. The vaccine may be able to trigger both a T-cell- and B-cell immune response. The present invention also relates to a kit comprising Vaccibody DNA, RNA, or protein for diagnostic, medical or scientific purposes.

The invention further relates to a method of preparing the recombinant molecule of the invention comprising, transfecting the vector comprising the molecule of the invention into a cell population; culturing the cell population; collecting recombinant protein expressed from the cell population; and purifying the expressed protein.

The above described nucleotide sequences may be inserted into a vector suited for gene therapy, e.g. under the control of a specific promoter, and introduced into the cells. In some embodiments the vector comprising said DNA sequence is a virus, e.g. an adenovirus, vaccinia virus or an adeno-associated virus. In some embodiments a retroviruses is used as vector. Examples of suitable retroviruses are e.g. MoMuLV or HaMuSV. For the purpose of gene therapy, the DNA/RNA sequences according to the invention can also be transported to the target cells in the form of colloidal dispersions. They comprise e.g. liposomes or lipoplexes.

The present invention encompasses the use of a targeting unit as well as an antigenic unit having minimum degree of sequence identity or sequence homology with amino acid sequence(s) defined herein or with a polypeptide having the specific properties defined herein. The present invention encompasses, in particular, the use of peptide variants or peptide units to be used in the constructs according to the present invention having a degree of sequence identity with any one of SEQ ID NO:l, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:ll, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:32, or SEQ ID NO:34. Here, the term "variant" means an entity having a certain degree of sequence identity with the subject amino acid sequences or the subject nucleotide sequences, where the subject amino acid sequence preferably is SEQ ID NO:l, SEQ ID NO:2, SEQ ID NO:3,

SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:ll, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, or SEQ ID NO:34.

In one aspect, the variant or fragment amino acid sequence and/or nucleotide sequence should provide and/or encode a polypeptide which retains the functional activity and/or enhances the activity of a polypeptide of SEQ ID NO:l, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:ll, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO : 19, SEQ ID NO : 21, SEQ ID NO : 22, SEQ ID NO : 23, SEQ ID NO : 24, SEQ ID NO : 25, SEQ ID NO : 26, SEQ ID NO : 27, SEQ ID NO : 28, SEQ ID NO : 29, SEQ ID NO : 30, SEQ ID NO : 32, or SEQ ID NO : 34.

In the present context, a variant sequence is taken to include an amino acid sequence which may be at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%, identical to the subject sequence. Typica lly, the variants used accord ing to the present invention will comprise the same active sites etc. as the subject amino acid sequence. Althoug h homology can also be considered in terms of similarity (i.e. amino acid residues having similar chemical properties/functions), in the context of the present invention it is preferred to express homology in terms of sequence identity.

Sequence identity comparisons can be conducted by eye, or more usually, with the aid of read ily available sequence comparison computer programs. These commercially available computer prog rams use complex comparison algorithms to alig n two or more sequences that best reflect the evolutionary events that might have led to the d ifference(s) between the two or more sequences. Therefore, these algorithms operate with a scoring system rewarding alig nment of identical or similar amino acids and penalising the insertion of gaps, gap extensions and alig nment of non-similar amino acids. The scoring system of the comparison algorithms include : i) assignment of a penalty score each time a gap is inserted (gap penalty score), ii) assignment of a penalty score each time an existing gap is extended with an extra position (extension penalty score), iii) assignment of high scores upon alignment of identical amino acids, and iv) assignment of variable scores upon alignment of non-identical amino acids.

Most alignment programs allow the gap penalties to be mod ified . However, it is preferred to use the default values when using such software for sequence comparisons.

The scores g iven for alig nment of non-identical amino acids are assigned accord ing to a scoring matrix also called a substitution matrix. The scores provided in such substitution matrices are reflecting the fact that the likelihood of one amino acid being substituted with another during evolution varies and depends on the physical/chemical nature of the amino acid to be substituted . For example, the likelihood of a polar amino acid being substituted with another polar amino acid is hig her compared to being substituted with a hydrophobic amino acid . Therefore, the scoring matrix will assign the hig hest score for identical amino acids, lower score for non-identical but similar amino acids and even lower score for non- identical non-similar amino acids. The most frequently used scoring matrices are the PAM matrices (Dayhoff et al. ( 1978), Jones et al. (1992)), the BLOSUM matrices (Henikoff and Henikoff (1992)) and the Gonnet matrix (Gonnet et al. (1992)) . Suitable computer prog rams for carrying out such an alig nment include, but are not limited to, Vector NTI (Invitrogen Corp.) and the ClustalV, ClustalW and ClustalW2 programs (H igg ins DG & Sharp PM (1988), H igg ins et al. (1992), Thompson et al. (1994), Larkin et al. (2007) . A selection of d ifferent alignment tools is available from the ExPASy Proteomics server at www.expasy.org . Another example of software that can perform sequence alig nment is BLAST (Basic Local Alig nment Search Tool), which is available from the webpage of National Center for Biotechnology Information which can currently be fou nd at

http ://www. ncbi. nlm. nih.gov/ and which was firstly described in Altschul et al. (1990) J . Mol. Biol. 215; 403-410.

Once the software has produced an alig nment, it is possible to calculate % similarity and % sequence identity. The software typically does this as part of the sequence comparison and generates a numerical result.

In one embodiment, it is preferred to use the ClustalW software for performing sequence alig nments. Preferably, alignment with ClustalW is performed with the following parameters for pairwise alignment:

ClustalW2 is for example made available on the internet by the European Bioinformatics Institute at the EM BL-EBI webpage www.ebi.ac.uk under tools - sequence analysis - ClustalW2. Currently, the exact add ress of the ClustalW2 tool is

www.ebi.ac.uk/Tools/clustalw2. In another embod iment, it is preferred to use the program Alig n X in Vector NTI (Invitrogen) for performing sequence alig nments. In one embod iment, ExplO has been may be used with default settings :

Gap opening penalty : 10

Gap extension penalty : 0.05

Gapseparation pena lty range : 8

Score matrix : blosum62mt2 Thus, the present invention also encompasses the use of variants, fragments, and derivatives of any amino acid sequence of a protein, polypeptide, motif or domain as defined herein, particularly those of SEQ ID NO:l, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:ll, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:32, or SEQ ID NO:34.

The sequences, particularly those of variants, fragments, and derivatives of SEQ ID NO:l, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:ll, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID

NO:29, SEQ ID NO:30, SEQ ID NO:32, or SEQ ID NO:34, may also have deletions, insertions or substitutions of amino acid residues which produce a silent change and result in a functionally equivalent substance. Deliberate amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues as long as the secondary binding activity of the substance is retained. For example, negatively charged amino acids include aspartic acid and glutamic acid; positively charged amino acids include lysine and arginine; and amino acids with uncharged polar head groups having similar hydrophilicity values include leucine, isoleucine, valine, glycine, alanine, asparagine, glutamine, serine, threonine, phenylalanine, and tyrosine.

The present invention also encompasses conservative substitution (substitution and replacement are both used herein to mean the interchange of an existing amino acid residue, with an alternative residue) that may occur i.e. like-for-like substitution such as basic for basic, acidic for acidic, polar for polar etc. Non-conservative substitution may also occur i.e. from one class of residue to another or alternatively involving the inclusion of unnatural amino acids such as ornithine (hereinafter referred to as Z), diaminobutyric acid ornithine (hereinafter referred to as B), norleucine ornithine (hereinafter referred to as O),

pyriylalanine, thienylalanine, naphthylalanine and phenylglycine.

Conservative substitutions that may be made are, for example within the groups of basic amino acids (Arginine, Lysine and Histidine), acidic amino acids (glutamic acid and aspartic acid), aliphatic amino acids (Alanine, Valine, Leucine, Isoleucine), polar amino acids

(Glutamine, Asparagine, Serine, Threonine), aromatic amino acids (Phenylalanine,

Tryptophan and Tyrosine), hydroxyl amino acids (Serine, Threonine), large amino acids (Phenylalanine and Tryptophan) and small amino acids (Glycine, Alanine). Replacements may also be made by unnatural amino acids include; alpha* and alpha- disubstituted* amino acids, N-alkyl amino acids*, lactic acid*, halide derivatives of natural amino acids such as trifluorotyrosine*, p-CI-phenylalanine*, p-Br-phenylalanine*, p-I- phenylalanine*, L-allyl-glycine*, β-alanine*, L-a-amino butyric acid*, L-y-amino butyric acid*, L-a-amino isobutyric acid*, L-e-amino caproic acid*, 7-amino heptanoic acid*, L- methionine sulfone*^*, L-norleucine*, L-norvaline*, p-nitro-L-phenylalanine*, L- hydroxyproline*, L-thioproline*, methyl derivatives of phenylalanine (Phe) such as 4-methyl- Phe*, pentamethyl-Phe*, L-Phe (4-amino) , L-Tyr (methyl)*, L-Phe (4-isopropyl)*, L-Tic (l,2,3,4-tetrahydroisoquinoline-3-carboxyl acid)*, L-diaminopropionic acid * and L-Phe (4- benzyl)*. The notation * has been utilised for the purpose of the discussion above (relating to homologous or non-conservative substitution), to indicate the hydrophobic nature of the derivative whereas # has been utilised to indicate the hydrophilic nature of the derivative, #* indicates amphipathic characteristics.

Variant amino acid sequences may include suitable spacer groups that may be inserted between any two amino acid residues of the sequence including alkyl groups such as methyl, ethyl or propyl groups in addition to amino acid spacers such as glycine or β-alanine residues.

A further form of variation, involves the presence of one or more amino acid residues in peptoid form, will be well understood by those skilled in the art. For the avoidance of doubt,

"the peptoid form" is used to refer to variant amino acid residues wherein the oc-carbon substituent group is on the residue's nitrogen atom rather than the oc-carbon. Processes for preparing peptides in the peptoid form are known in the art, for example Simon RJ et al.

(1992), Horwell DC. (1995).

In one embodiment, the variant targeting unit used in the homodimeric protein according to the present invention is variant having the sequence of amino acids at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% amino acid sequence identity therewith.

In one aspect, preferably the protein or sequence used in the present invention is in a purified form. The term "purified" means that a given component is present at a high level. The component is desirably the predominant active component present in a composition. A "variant" or "variants" refers to proteins, polypeptides, units, motifs, domains or nucleic acids. The term "variant" may be used interchangeably with the term "mutant." Variants include insertions, substitutions, transversions, truncations, and/or inversions at one or more locations in the amino acid or nucleotide sequence, respectively. The phrases "variant polypeptide", "polypeptide", "variant" and "variant enzyme" mean a polypeptide/protein that has an amino acid sequence that has been modified from the amino acid sequence of SEQ ID NO: 1. The variant polypeptides include a polypeptide having a certain percent, e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, of sequence identity with the amino acid sequence of SEQ ID NO:l, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:ll, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID

NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:32, or SEQ ID NO:34.

"Variant nucleic acids" can include sequences that are complementary to sequences that are capable of hybridizing to the nucleotide sequences presented herein. For example, a variant sequence is complementary to sequences capable of hybridizing under stringent conditions, e.g., 50°C and 0.2X SSC (IX SSC = 0.15 M NaCI, 0.015 M sodium citrate, pH 7.0), to the nucleotide sequences presented herein. More particularly, the term variant encompasses sequences that are complementary to sequences that are capable of hybridizing under highly stringent conditions, e.g., 65°C and 0.1X SSC, to the nucleotide sequences presented herein. The melting point (Tm) of a variant nucleic acid may be about 1, 2, or 3°C lower than the Tm of the wild-type nucleic acid. The variant nucleic acids include a polynucleotide having a certain percent, e.g., 80%, 85%, 90%, 95%, or 99%, of sequence identity with the nucleic acid encoding SEQ ID NO:l, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:ll, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID

NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:32, or SEQ ID NO:34, encoding the monomeric protein which can form the homodimeric protein according to invention.

A specific category of mutations are the mutations in E6 and E7: The E6 protein may be detoxified by rendering the p53 binding impossible. Five positions in the full length HPV16 E6 protein are sites for mutations for inactivation of E6 functionality, F47, L50, C63, C106 and 1128. Any amino acid substitution in these positions may lead to inactivation of E6 and induces tumor suppression. Substitutions in any one of these positions with any one different amino acid may potentially be utilized. Sites for potential mutations are shown in SEQ ID NO:22.

In the E7 protein there are conserved regions associated with oncogenic properties (see Phelps et al J. Virol. April 1992, vol.66, no.42418-242; Gulliver et al J Virol.1997,

August; 71(8)) including an N-terminal Rb (retinoblastoma binding protein) binding-site motif (LXCXE) and two conserved regions 3 (upstream and downstream) with a Zn- binding motif (CXXC). The preferred mutation sites in the LXCXE-motif are C24 and E26. Preferred sites in the two CXXC motifs are C58, C61, C91 and C94. However, any mutations in these reg ions can be envisaged to be substituted for the reduction of bind ing functions and thus abolish the oncogenic effects of E7. Sites for potential mutations are shown in SEQ ID NO : 23.

Signal peptide : A sig nal peptide at the N-terminal end of the nascent polypeptide d irects the molecu le into the ER before transport to into the Golgi complex. The signal peptide is cleaved off by sig nal peptidase once it has served its purpose of targeting and importing the protein to the ER. These signal peptides are generally between 15 and 30 amino acids, but can have more than 50 residues (Martoglio, B. et al., Trends in Cell Biology, 1998, Knappskog, S. et al., J

Biotechnol, 2007). The native signal peptide may be replaced by signal peptides from any mammalian, prokaryotic or marine origin. Commonly used sig nal peptides are e.g . humanlL- 2 and human albumin due to their natural ability to secrete large amounts of protein. The choice of sig nal peptide can have a considerable impact on the amount of synthesized and secreted protein. In some embodiments, the sig nal peptide used in the protein construct accord ing to the present invention is derived from a chemokine protein, such as the signal sequence of LD78beta.

In some embodiments the signal peptide is not derived from pLNOH2 (Bl-8 variable immunog lobulin leader) d isclosed in the international application with International

Application No : PCT/EP2011/060628.

In some embodiments the signal peptide is not derived from an immunog lobulin gene.

The term "homodimeric protein" as used herein refers to a protein comprising two ind ividual identical strands of amino acids, or subunits held together as a sing le, d imeric protein by hydrogen bond ing, ionic (charged) interactions, actual covalent disulfide bonding, or some combination of these interactions.

The term "dimerization motif", as used herein, refers to the sequence of amino acids between the antigenic unit and the targeting unit comprising the hinge reg ion and the optional second domain that may contribute to the d imerization. This second domain may be an

immunog lobulin domain, and optionally the hinge region and the second domain are connected throug h a linker. According ly the d imerization motif serves to connect the antigenic unit and the targeting unit, but also contain the hinge region that facilitates the dimerization of the two monomeric proteins into a homod imeric protein accord ing to the invention. The term "targeting unit" as used herein refers to a unit that delivers the protein with its antigen to mouse or human APC for MHC class Il-restricted presentation to CD4+ T cells or for provid ing cross presentation to CD8+ T cells by M HC class I restriction. The targeting unit used in the constructs accord ing to the present invention is derived from or identical to mature LD78-beta.

The term "antigenic unit" as used herein refers to any molecule, such as a peptide which is able to be specifically recognized by an antibody or other component of the immune system, such as a surface receptor on T-cells. Included within this definition are also immunogens that are able to induce an immune response. The terms "epitope" or "antigenic epitope" is used to refer to a distinct molecular surface, such as a molecular surface provided by a short peptide sequence within an antigenic unit. In some embod iments the antigenic unit comprises two ore more antigenic epitopes. The antigenic unit used in the constructs accord ing to the present invention is derived from or identical to the early gene products E6 and E7 from H PV, such as from HPV16 or HPV18. The term "hinge region" refers to a peptide sequence of the homod imeric protein that facilitates the d imerization, such as throug h the formation of an interchain covalent bond(s), e.g . d isulfide bridge(s) . The hinge reg ion may be Ig derived, such as hinge exons hl + h4 of an Ig, such as IgG3.

Specific embodiments of the invention: As described above, the present invention relates to a homod imeric protein of two identical amino acid chains, each amino acid chain comprising (1) a sig nal peptide, (2) a targeting unit, (3) a dimerization motif, and (4) an antigenic unit, said targeting unit comprising an amino acid sequence having at least 80 % sequence identity to the amino acid sequence 24- 93 of SEQ ID NO : l, and an antigenic unit comprising an am ino acid sequence of human papillomavirus (HPV), such as an antigenic unit comprising an amino acid sequence of H PV16 and/or H PV18, such as an antigenic unit derived from early proteins E6 and/or E7 of H PV16 and/or H PV18. In some embod iments accord ing to the present invention, the targeting unit, d imerization motif and antigenic unit in the amino acid chain are in the N-terminal to C- terminal order of targeting unit, d imerization motif and antigenic unit. In some embodiments, the antigenic unit used in the constructs accord ing to the present invention is derived from H PV16, such as from early proteins E6 and/or E7. In some embodiments, the antigenic unit used in the constructs according to the present invention is derived from E6 of HPV16.

In some embodiments, the antigenic unit used in the constructs according to the present invention is derived from E7 of HPV16. In some embodiments, the antigenic unit used in the constructs according to the present invention is derived from HPV18, such as from early proteins E6 and/or E7.

In some embodiments, the antigenic unit used in the constructs according to the present invention is derived from E6 of HPV18.

In some embodiments, the antigenic unit used in the constructs according to the present invention is derived from E7 of HPV18.

In some embodiments according to the present invention, the signal peptide consists of an amino acid sequence having at least 80 % sequence identity to the amino acid sequence 1- 23 of SEQ ID NO:l.

In some embodiments according to the present invention, the signal peptide consists of an amino acid sequence having at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% sequence identity to the amino acid sequence 1-23 of SEQ ID NO:l. In some embodiments according to the present invention, the targeting unit consists of an amino acid sequence having at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% sequence identity to the amino acid sequence 24-93 of SEQ ID NO:l.

In some embodiments according to the present invention, the dimerization motif comprises a hinge region and optionally another domain that facilitate dimerization, such as an immunoglobulin domain, optionally connected through a linker. In some embodiments according to the present invention, the hinge region is Ig derived, such as derived from IgG3.

In some embodiments according to the present invention, the hinge region has the ability to form one, two, or several covalent bonds. In some embod iments accord ing to the present invention, the covalent bond is a d isulphide bridge.

In some embodiments according to the present invention, the immunog lobulin domain of the d imerization motif is a carboxyterminal C domain, or a sequence that is substantially identical to the C doma in or a variant thereof.

In some embodiments according to the present invention, the carboxyterminal C domain is derived from IgG.

In some embodiments according to the present invention, the immunog lobulin domain of the d imerization motif has the ability to homod imerize.

In some embodiments according to the present invention, the immunog lobulin domain has the ability to homod imerize via noncovalent interactions. In some embod iments according to the present invention, the noncovalent interactions are hydrophobic interactions.

In some embodiments according to the present invention, the d imerization domain does not comprise the CH2 domain.

In some embodiments according to the present invention, the d imerization motif consists of hinge exons hi and h4 connected throug h a linker to a C_H3 domain of human IgG3. In some embodiments according to the present invention, the d imerization motif consist of an amino acid sequence having at least 80 % sequence identity to the amino acid sequence 94-237 of SEQ ID NO : 3.

In some embodiments according to the present invention, the linker is a G₃S₂G₃SG linker.

In some embodiments according to the present invention, the antigenic u nit and the d imerization motif is connected through a linker, such as a GLGGL linker or a GLSGL linker.

In some embodiments according to the present invention, the targeting unit consists of amino acids 24-93 of SEQ ID NO : l, or a variant thereof. In some embodiments according to the present invention, the homod imeric protein have increased affinity for any one chemokine receptor selected from CCR1, CCR3 and CCR5 as compared to the affinity of the same homod imeric protein with the targeting unit consisting of amino acids 24-93 of SEQ ID NO : l, or a variant thereof. In some embodiments according to the present invention, the antigenic u nit comprises an amino acid sequence having at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% sequence identity to the amino acid sequence 243-293 of SEQ ID NO : 3.

In some embodiments according to the present invention, the antigenic u nit consists of an amino acid sequence having at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% sequence identity to the amino acid sequence 243-293 of SEQ ID NO : 3.

In some embodiments according to the present invention, the antigenic u nit comprises one or more amino acid substitutions at a position selected from the list consisting of F47, L50, C63, C106 and 1128 of SEQ ID NO : 22, or a deletion involving one or more amino acid selected from the list consisting of Y43-L50 of SEQ ID NO : 22.

In some embodiments according to the present invention, the antigenic u nit comprises not more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18 or 20 amino acid su bstitutions and/or deletions relative to SEQ ID NO : 22.

In some embodiments according to the present invention, the antigenic u nit comprises the amino acid sequence 243-293 of SEQ ID NO : 3, SEQ ID NO : 5, SEQ ID NO : 7, or SEQ ID NO :9, or a variant or antigenic fragment thereof.

In some embodiments according to the present invention, the antigenic u nit consists of the amino acid sequence 243-293 of SEQ ID NO : 3, SEQ ID NO : 5, SEQ ID NO : 7, or SEQ ID NO :9, or a variant or antigenic fragment thereof. In some embodiments according to the present invention, the antigenic u nit comprises an amino acid sequence having at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% sequence identity to the amino acid sequence 243-340 of SEQ ID NO : 11.

In some embodiments according to the present invention, the antigenic u nit consists of an amino acid sequence having at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% sequence identity to the amino acid sequence 243-340 of SEQ ID NO : 11. In some embodiments according to the present invention, the antigenic u nit comprises one or more amino acid substitutions at a position selected from the list consisting of C24, E26, C58, C61, C91, and C94 of SEQ ID NO : 23, or a deletion involving one or more amino acid selected from the list consisting of L22-E26 and/or C58-C61 and/or C91-S95 of SEQ ID NO : 23.

In some embodiments according to the present invention, the antigenic u nit comprises not more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18 or 20 amino acid su bstitutions and/or deletions relative to SEQ ID NO : 23.

In some embodiments according to the present invention, the antigenic u nit comprises the amino acid sequence 243-340 of SEQ ID NO : l l, SEQ ID NO : 13, SEQ ID NO : 15, or SEQ ID NO : 17, or a variant or antigenic fragment thereof. In some embodiments according to the present invention, the antigenic u nit consists of the amino acid sequence 243-340 of SEQ ID NO : l l, SEQ ID NO : 13, SEQ ID NO : 15, or SEQ ID NO : 17, or a variant or antigenic fragment thereof.

In some embodiments according to the present invention, the antigenic u nit comprises an amino acid sequence having at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% sequence identity to the amino acid sequence 243-501 of SEQ ID NO: 19, SEQ ID NO:21, SEQ ID NO:32, or SEQ ID NO:34.

In some embodiments according to the present invention, the antigenic unit consists of an amino acid sequence having at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% sequence identity to the amino acid sequence 243-501 of SEQ ID NO: 19, SEQ ID NO:21, SEQ ID NO:32, or SEQ ID NO:34.

In some embodiments according to the present invention, the antigenic unit comprising an amino acid sequence of human papillomavirus 16 (HPV16) derived from both early proteins E6 and E7.

In some embodiments according to the present invention, the antigenic unit comprising an amino acid sequence of human papillomavirus 18 (HPV18) derived from both early proteins E6 and E7.

In some embodiments according to the present invention, the antigenic unit comprises one or more amino acid substitutions at a position selected from the list consisting of F47, L50G, C63, C106, I128T of SEQ ID NO:22 and C24, E26, C58, C61, C91, C94 of SEQ ID NO:23. In some embodiments according to the present invention, the antigenic unit comprises not more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18 or 20 amino acid substitutions and/or deletions relative to SEQ ID NO:22 and SEQ ID NO:23.

In some embodiments according to the present invention, the antigenic unit consists of the amino acid sequence 243-501 of SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:32, or SEQ ID NO:34, or a variant or antigenic fragment thereof.

In some embodiments according to the present invention, the amino acid chain consists of an amino acid sequence selected from the list consisting of SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:ll, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:32, and SEQ ID NO:34, or a variant or antigenic fragment thereof. In some embodiments according to the present invention, the antigenic unit comprises an amino acid sequence having at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% sequence identity to any one amino acid sequence selected from SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, and SEQ ID NO:25.

In some embodiments according to the present invention, the antigenic unit consist of an amino acid sequence having at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% sequence identity to any one amino acid sequence selected from SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, and SEQ ID NO:25.

In some embodiments the homodimeric protein according to the present invention, is in its mature form without any signal peptide sequence.

In some embodiments the nucleic acid molecule according to the present invention is human codon optimized.

It is to be understood that a human codon optimized nucleic acid molecule according to the present invention comprises one or more nucleic acid substitution as compared to the wild type sequence, which substitution provides for a codon with higher frequency of usage in human coding regions. Frequency of codon usage in homo sapiens can be found at http://biowiki.edu-wiki.org/en/codon_table

In some embodiments the nucleic acid molecule according to the present invention is comprising any one of nucleotide sequences selected from the list consisting of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:31 and SEQ ID NO:33, or a variant thereof.

In some embodiments the nucleic acid molecule according to the present invention is comprised by a vector. In some embodiments the nucleic acid molecule according to the present invention is formulated for administration to a patient to induce production of the homodimeric protein in said patient.

In some embodiments the vaccine according to the present invention further comprises a pharmaceutically acceptable carrier and/or adjuvant.

In some embodiments, the method of treating or preventing a HPV induced disease or condition, such as a cancer or an infectious disease caused by HPV in a patient according to the present invention comprises administering to the patient in need thereof of a nucleic acid molecule, such as a DNA, according to the present invention with a subsequent step of electroporation. In some embodiments the administration is performed intra dermal or intra muscular.

EXAMPLE 1

Construction and expression of the vaccines.

Gene sequences were designed according to the following structure: 1: native leader sequence for human LD78 b, 2: full length LD78b sequence.3: Human hinge-region 1 from IgG3.4: Human hinge region 4 from IgG3.5: Glycine- Serine linker.6: Human CH3 domain from IgG3.7: Glycine-Leucine linker.8: wildtype and mutant Human papilloma virus oncogenes E6, E7 and fusion proteins of both E6 and E7 divided by a Glycine- Serine linker. The constructs are designated according to their E6 and or E7 composition as follows:

VB1001: Vaccibody-E6 wild type;

VB1005: Vaccibody-E7 wild type;

The mutants are designated according to the amino acid position in the corresponding native E6 or E7 sequence.

VB1002: Vaccibody-E6 C63R;

VB1003: Vaccibody-E6 C106R;

VB1004: Vaccibody-E6 F47R, C63R, C106R;

VB1006: Vaccibody-E7 C24G, E26G;

VB1007: Vaccibody-E7 C24G, E26G, C58G, C61G;

VB1008: Vaccibody-E7 C24G, E26G, C91G, C94G;

VB1009: Vaccibody- E7 C24G, E26G/ E6 F47R, C63R, C106R; VB1016 : Vaccibody- E7 C24G, E26G/ E6 C63R, C106R;

VB1020 : Vaccibody- E7 C24G, E26G/ E6 F47R, C63R, C106R human codon optimized VB1021 : Vaccibody- E7 C24G, E26G/ E6 F47R, L50G, C106R, I128T human codon optimized

Control vaccines composed of only the antigens were included :

Control 1 : E7 C24G, E26G/ E6 F47R, C63R, C106R;

Control 2 : E7 C24G, E26G/ E6 C63R, C106R

All gene sequences were ordered from Aldevron (Fargo ND, USA) or Eurofins MWG GmbH and cloned into the expression vector pUMVC4a.

All constructs were transfected in to 293E cells and verified expression of intact vaccibody proteins were performed by dot blot and ELISA (data not shown) . All am ino acid sequences except for Controls 1 and 2 are shown as SEQ IDs.

EXAM PLE 2.

Immune response studies

VB 1009,VB1016, VB1020 and VB1021 were selected as vaccine cand idates with their correspond ing controls 1 and 2 respectively. As a negative control empty pUMVC4a vector was utilized .

25, 12.5 and 1.4 pg plasmid DNA of each cand idate was injected intradermal in the lower back of C57BI/6 mice followed by electroporation, Dermavax, Cellectis (Paris, France) . 7 days later the mice were boosted with similar amounts of vaccines and control plasmids. At day 21 the mice were killed and spleens were harvested .

The T cell responses were calcu lated by ELISPOT. (Figures 3 a, b and c)

EXAM PLE 3.

Therapeutic effect

VB1016, VB1020 and VB1021 with the correspond ing controls 1 and 2 were selected as the vaccine cand idate for therapeutic vaccine studies.

5xl0⁴ or 5xl0⁵ TC-1 cells (Johns Hopkins University, Baltimore, USA, Lin KY et al., Cancer Res, 1996) were injected in the neck or thigh reg ion of C57BI/6 mice. After days 3 and 10 or day 3,7 and 10, the mice were vaccinated with 2pg, 10pg, 12.5 pg or 20pg of plasmid DNA followed by electroporation, Dermavax, Cellectis France. Tumor size were measured two to three times a week up until day 49 after TC-1 cell injection (Figure 4, 5 and 6)

EXAM PLE 4.

A therapeutic DNA vaccine to be used may be prepared by GM P manufactu ring of the plasmid vaccine accord ing to regulatory authorities' gu idelines, includ ing GMP cell banking, GM P manufactu ring of d rug substance and d rug product, ICH stability stud ies and Fill & Finish of the DNA vaccine. The DNA vaccine may be formulated by d issolving in a saline solution, such as ΙΟηΜ Tris, ImM EDTA at a concentration of 2-5 mg/ml. The vaccine may be administered either intra-derma l or intra-muscular with or without following electroporation.

SEQUENCES :

C-C motif chemokine 3-like 1 precursor including signal peptide (aa 1-23 in bold) and mature peptide (LD78-beta), aa 24-93 (SEQ ID NO : l) :

MQVSTAALAVLLCTMALCNQVLSAPLAADTPTACCFSYTSRQIPQNFIADYFETSSQCSKPSVIFLTKR

GRQVCADPSEEWVQKYVSDLELSA

The specific DNA and correspond ing amino acid sequences of vaccibody HPV constructs :

E6 or E7 single constructs:

For the purpose of illustration only, the d ifferent domains of the constructs are separated by an " I "with the domains in the following order: Sig nal peptide | human ΜΙΡ-Ια | Hinge hi | H inge h4 I Gly-Ser Linker or Gly-Leu I i n ke r | hCH3 IgG3 | Gly-Ser Linker or Gly-Leu I i n ke r | wildtype or mutant fu ll length E6 or E7. Amino acids or nucleotides in bold illustrates sites of mutations.

DNA sequence of VB1001 (SEQ ID NO : 2) :

ATGCAGGTCTCCACTGCTGCCCTTGCCGTCCTCCTCTGCACCATGGCTCTCTGCAACCAGGTCCTCTCT | GCACCACTT GCTGCTGACACGCCGACCGCCTGCTGCTTCAGCTACACCTCCCGACAGATTCCACAGAATTTCATAGCTGACTACTTTG AGACGAGCAGCCAGTGCTCCAAGCCCAGTGTCATCTTCCTAACCAAGAGAGGCCGGCAGGTCTGTGCTGACCCCAGTGA GGAGTGGGTCCAGAAATACGTCAGTGACCTGGAGCTGAGTGCC | GAGCTCAAAACCCCACTTGGTGACACAACTCACAC A I GAGCCCAAATCTTGTGACACACCTCCCCCGTGCCCAAGGTGCCCA | GGCGGTGGAAGCAGCGGAGGTGGAAGTGGA | GGACAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT GCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAGCGGGCAGCCGGAGAACAACTACAACAC CACGCCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAG GGGAACATCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCGCTTCACGCAGAAGAGCCTCTCCCTGTCTCCGG GTAAA I GGCCTCGGTGGCCTG | ATGTTTCAGGACCCACAGGAGCGACCCAGAAAGTTACCACAGTTATGCACAGAGCTG CAAACAACTATACATGATATAATATTAGAATGTGTGTACTGCAAGCAACAGTTACTGCGACGTGAGGTATATGACTTTG CTTTTCGGGATTTATGCATAGTATATAGAGATGGGAATCCATATGCTGTATGTGATAAATGTTTAAAGTTTTATTCTAA AATTAGTGAGTATAGACATTATTGTTATAGTTTGTATGGAACAACATTAGAACAGCAATACAACAAACCGTTGTGTGAT TTGTTAATTAGGTGTATTAACTGTCAAAAGCCACTGTGTCCTGAAGAAAAGCAAAGACATCTGGACAAAAAGCAAAGAT TCCATAATATAAGGGGTCGGTGGACCGGTCGATGTATGTCTTGTTGCAGATCATCAAGAACACGTAGAGAAACCCAGCT GTAA Protein sequence of VB1001 (Homod imeric construct accord ing to the invention with E6, SEQ ID NO : 3) : Amino acid sequence 393 amino acids.

MQVSTAALAVLLCTMALCNQVLS | APLAADTPTACCFSYTSRQIPQNFIAD

YFETSSQCSKPSVIFLTKRGRQVCADPSEEWVQKYVSDLELSA | ELKTPLG

DTTHT I EPKSCDTPPPCPRCP | GGGSSGGGSG | GQPREPQVYTLPPSREEMTK

NQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKL TVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPGK | GLGGL | MFQDPQER

PRKLPQLCTELQTTIHDIILECVYCKQQLLRREVYDFAFRDLCIVYRDGN PYAVCDKCLKFYSKISEYRHYCYSLYGTTLEQQYNKPLCDLLIRCINCQK PLCPEEKQRHLDKKQRFHNIRGRWTGRCMSCCRSSRTRRETQL*

DNA sequence of VB1002 (SEQ ID NO :4) :

ATGCAGGTCTCCACTGCTGCCCTTGCCGTCCTCCTCTGCACCATGGCTCTCTGCAACCAGGTCCTCTCT | GCACCACTT GCTGCTGACACGCCGACCGCCTGCTGCTTCAGCTACACCTCCCGACAGATTCCACAGAATTTCATAGCTGACTACTTTG AGACGAGCAGCCAGTGCTCCAAGCCCAGTGTCATCTTCCTAACCAAGAGAGGCCGGCAGGTCTGTGCTGACCCCAGTGA GGAGTGGGTCCAGAAATACGTCAGTGACCTGGAGCTGAGTGCC | GAGCTCAAAACCCCACTTGGTGACACAACTCACAC A I GAGCCCAAATCTTGTGACACACCTCCCCCGTGCCCAAGGTGCCCA | GGCGGTGGAAGCAGCGGAGGTGGAAGTGGA | GGACAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT GCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAGCGGGCAGCCGGAGAACAACTACAACAC CACGCCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAG GGGAACATCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCGCTTCACGCAGAAGAGCCTCTCCCTGTCTCCGG GTAAA I GGCCTCGGTGGCCTG | ATGTTTCAGGACCCACAGGAGCGACCCAGAAAGTTACCACAGTTATGCACAGAGCTG CAAACAACTATACATGATATAATATTAGAATGTGTGTACTGCAAGCAACAGTTACTGCGACGTGAGGTATATGACTTTG CTTTTCGGGATTTATGCATAGTATATAGAGATGGGAATCCATATGCTGTACGAGATAAATGTTTAAAGTTTTATTCTAA AATTAGTGAGTATAGACATTATTGTTATAGTTTGTATGGAACAACATTAGAACAGCAATACAACAAACCGTTGTGTGAT TTGTTAATTAGGTGTATTAACTGTCAAAAGCCACTGTGTCCTGAAGAAAAGCAAAGACATCTGGACAAAAAGCAAAGAT TCCATAATATAAGGGGTCGGTGGACCGGTCGATGTATGTCTTGTTGCAGATCATCAAGAACACGTAGAGAAACCCAGCT GTAA Protein sequence of VB1002 (Homod imeric construct accord ing to the invention, SEQ ID NO : 5) : Amino acid sequence, 393 amino acids.

MQVSTAALAVLLCTMALCNQVLS | APLAADTPTACCFSYTSRQIPQNFIAD

YFETSSQCSKPSVIFLTKRGRQVCADPSEEWVQKYVSDLELSA | ELKTPLG

DTTHT I EPKSCDTPPPCPRCP | GGGSSGGGSG | GQPREPQVYTLPPSREEMTK

NQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKL

TVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPGK | GLGGL | MFQDPQER

PRKLPQLCTELQTTIHDI ILECVYCKQQLLRREVYDFAFRDLCIVYRDGN PYAVRDKCLKFYSKISEYRHYCYSLYGTTLEQQYNKPLCDLLIRCINCQK PLCPEEKQRHLDKKQRFHNIRGRWTGRCMSCCRSSRTRRETQL*

DNA sequence of VB 1003 (SEQ ID NO : 6) :

ATGCAGGTCTCCACTGCTGCCCTTGCCGTCCTCCTCTGCACCATGGCTCTCTGCAACCAGGTCCTCTCT | GCACCACTT GCTGCTGACACGCCGACCGCCTGCTGCTTCAGCTACACCTCCCGACAGATTCCACAGAATTTCATAGCTGACTACTTTG AGACGAGCAGCCAGTGCTCCAAGCCCAGTGTCATCTTCCTAACCAAGAGAGGCCGGCAGGTCTGTGCTGACCCCAGTGA GGAGTGGGTCCAGAAATACGTCAGTGACCTGGAGCTGAGTGCC | GAGCTCAAAACCCCACTTGGTGACACAACTCACAC A I GAGCCCAAATCTTGTGACACACCTCCCCCGTGCCCAAGGTGCCCA | GGCGGTGGAAGCAGCGGAGGTGGAAGTGGA | GGACAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT GCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAGCGGGCAGCCGGAGAACAACTACAACAC CACGCCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAG GGGAACATCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCGCTTCACGCAGAAGAGCCTCTCCCTGTCTCCGG GTAAA I GGCCTCGGTGGCCTG | ATGTTTCAGGACCCACAGGAGCGACCCAGAAAGTTACCACAGTTATGCACAGAGCTG CAAACAACTATACATGATATAATATTAGAATGTGTGTACTGCAAGCAACAGTTACTGCGACGTGAGGTATATGACTTTG CTTTTCGGGATTTATGCATAGTATATAGAGATGGGAATCCATATGCTGTATGTGATAAATGTTTAAAGTTTTATTCTAA AATTAGTGAGTATAGACATTATTGTTATAGTTTGTATGGAACAACATTAGAACAGCAATACAACAAACCGTTGTGTGAT TTGTTAATTAGGTGTATTAACCGACAAAAGCCACTGTGTCCTGAAGAAAAGCAAAGACATCTGGACAAAAAGCAAAGAT TCCATAATATAAGGGGTCGGTGGACCGGTCGATGTATGTCTTGTTGCAGATCATCAAGAACACGTAGAGAAACCCAGCT GTAA Protein sequence of VB1003 (Homod imeric construct accord ing to the invention, SEQ ID NO : 7) : Amino acid sequence, 393 amino acids.

MQVSTAALAVLLCTMALCNQVLS | APLAADTPTACCFSYTSRQIPQNFIAD

YFETSSQCSKPSVIFLTKRGRQVCADPSEEWVQKYVSDLELSA | ELKTPLG

DTTHT I EPKSCDTPPPCPRCP | GGGSSGGGSG | GQPREPQVYTLPPSREEMTK

PRKLPQLCTELQTTIHDI ILECVYCKQQLLRREVYDFAFRDLCIVYRDGN PYAVCDKCLKFYSKISEYRHYCYSLYGTTLEQQYNKPLCDLLIRCINRQK PLCPEEKQRHLDKKQRFHNIRGRWTGRCMSCCRSSRTRRETQL*

DNA sequence of VB1004 (SEQ ID NO :8) :

ATGCAGGTCTCCACTGCTGCCCTTGCCGTCCTCCTCTGCACCATGGCTCTCTGCAACCAGGTCCTCTCT | GCACCACTT GCTGCTGACACGCCGACCGCCTGCTGCTTCAGCTACACCTCCCGACAGATTCCACAGAATTTCATAGCTGACTACTTTG AGACGAGCAGCCAGTGCTCCAAGCCCAGTGTCATCTTCCTAACCAAGAGAGGCCGGCAGGTCTGTGCTGACCCCAGTGA GGAGTGGGTCCAGAAATACGTCAGTGACCTGGAGCTGAGTGCC | GAGCTCAAAACCCCACTTGGTGACACAACTCACAC A I GAGCCCAAATCTTGTGACACACCTCCCCCGTGCCCAAGGTGCCCA | GGCGGTGGAAGCAGCGGAGGTGGAAGTGGA | GGACAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT GCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAGCGGGCAGCCGGAGAACAACTACAACAC CACGCCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAG GGGAACATCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCGCTTCACGCAGAAGAGCCTCTCCCTGTCTCCGG GTAAA I GGCCTCGGTGGCCTG | ATGTTTCAGGACCCACAGGAGCGACCCAGAAAGTTACCACAGTTATGCACAGAGCTG CAAACAACTATACATGATATAATATTAGAATGTGTGTACTGCAAGCAACAGTTACTGCGACGTGAGGTATATGACTTTG CTCGACGGGATTTATGCATAGTATATAGAGATGGGAATCCATATGCTGTACGAGATAAATGTTTAAAGTTTTATTCTAA AATTAGTGAGTATAGACATTATTGTTATAGTTTGTATGGAACAACATTAGAACAGCAATACAACAAACCGTTGTGTGAT TTGTTAATTAGGTGTATTAACCGACAAAAGCCACTGTGTCCTGAAGAAAAGCAAAGACATCTGGACAAAAAGCAAAGAT TCCATAATATAAGGGGTCGGTGGACCGGTCGATGTATGTCTTGTTGCAGATCATCAAGAACACGTAGAGAAACCCAGCT GTAA

Protein sequence of VB1004 (Homod imeric construct accord ing to the invention, SEQ ID NO :9) : Amino acid sequence, 393 amino acids.

MQVSTAALAVLLCTMALCNQVLSAPLAADTPTACCFSYTSRQIPQNFIAD YFETSSQCSKPSVIFLTKRGRQVCADPSEEWVQKYVSDLELSAELKTPLG DTTHTEPKSCDTPPPCPRCPGGGSSGGGSGGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKL TVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPGKGLGGLMFQDPQER PRKLPQLCTELQTTIHDI ILECVYCKQQLLRREVYDFARRDLCIVYRDGN PYAVRDKCLKFYSKISEYRHYCYSLYGTTLEQQYNKPLCDLLIRCINRQK PLCPEEKQRHLDKKQRFHNIRGRWTGRCMSCCRSSRTRRETQL* DNA sequence of VB1005 (SEQ ID NO : 10) :

ATGCAGGTCTCCACTGCTGCCCTTGCCGTCCTCCTCTGCACCATGGCTCTCTGCAACCAGGTCCTCTCT | GCACCACTT GCTGCTGACACGCCGACCGCCTGCTGCTTCAGCTACACCTCCCGACAGATTCCACAGAATTTCATAGCTGACTACTTTG AGACGAGCAGCCAGTGCTCCAAGCCCAGTGTCATCTTCCTAACCAAGAGAGGCCGGCAGGTCTGTGCTGACCCCAGTGA GGAGTGGGTCCAGAAATACGTCAGTGACCTGGAGCTGAGTGCC | GAGCTCAAAACCCCACTTGGTGACACAACTCACAC A I GAGCCCAAATCTTGTGACACACCTCCCCCGTGCCCAAGGTGCCCA | GGCGGTGGAAGCAGCGGAGGTGGAAGTGGA | GGACAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT GCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAGCGGGCAGCCGGAGAACAACTACAACAC CACGCCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAG GGGAACATCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCGCTTCACGCAGAAGAGCCTCTCCCTGTCTCCGG GTAAA I GGCCTCGGTGGCCTG | ATGCATGGAGATACACCTACATTGCATGAATATATGTTAGATTTGCAACCAGAGACA ACTGATCTCTACTGTTATGAGCAATTAAATGACAGCTCAGAGGAGGAGGATGAAATAGATGGTCCAGCTGGACAAGCAG AACCGGACAGAGCCCATTACAATATTGTAACCTTTTGTTGCAAGTGTGACTCTACGCTTCGGTTGTGCGTACAAAGCAC ACACGTAGACATTCGTACTTTGGAAGACCTGTTAATGGGCACACTAGGAATTGTGTGCCCCATCTGTTCTCAGAAACCA TAA Protein sequence of VB1005 (Homod imeric construct accord ing to the invention with E7, SEQ ID NO : l l) : Am ino acid seq uence, 340 am ino acids.

MQVSTAALAVLLCTMALCNQVLS | APLAADTPTACCFSYTSRQIPQNFIAD

YFETSSQCSKPSVIFLTKRGRQVCADPSEEWVQKYVSDLELSA | ELKTPLG

DTTHT I EPKSCDTPPPCPRCP | GGGSSGGGSG | GQPREPQVYTLPPSREEMTK

NQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKL TVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPGK | GLGGL | MHGDTPTL

HEYMLDLQPETTDLYCYEQLNDSSEEEDEIDGPAGQAEPDRAHYNIVTFC CKCDSTLRLCVQSTHVDIRTLEDLLMGTLGIVCPICSQKP*

DNA seq uence of VB1006 (SEQ ID NO : 12) :

ATGCAGGTCTCCACTGCTGCCCTTGCCGTCCTCCTCTGCACCATGGCTCTCTGCAACCAGGTCCTCTCT | GCACCACTT GCTGCTGACACGCCGACCGCCTGCTGCTTCAGCTACACCTCCCGACAGATTCCACAGAATTTCATAGCTGACTACTTTG AGACGAGCAGCCAGTGCTCCAAGCCCAGTGTCATCTTCCTAACCAAGAGAGGCCGGCAGGTCTGTGCTGACCCCAGTGA GGAGTGGGTCCAGAAATACGTCAGTGACCTGGAGCTGAGTGCC | GAGCTCAAAACCCCACTTGGTGACACAACTCACAC A I GAGCCCAAATCTTGTGACACACCTCCCCCGTGCCCAAGGTGCCCA | GGCGGTGGAAGCAGCGGAGGTGGAAGTGGA | GGACAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT GCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAGCGGGCAGCCGGAGAACAACTACAACAC CACGCCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAG GGGAACATCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCGCTTCACGCAGAAGAGCCTCTCCCTGTCTCCGG GTAAA I GGCCTCGGTGGCCTG | ATGCATGGAGATACACCTACATTGCATGAATATATGTTAGATTTGCAACCAGAGACA ACTGATCTCTACGGATATGGACAATTAAATGACAGCTCAGAGGAGGAGGATGAAATAGATGGTCCAGCTGGACAAGCAG AACCGGACAGAGCCCATTACAATATTGTAACCTTTTGTTGCAAGTGTGACTCTACGCTTCGGTTGTGCGTACAAAGCAC ACACGTAGACATTCGTACTTTGGAAGACCTGTTAATGGGCACACTAGGAATTGTGTGCCCCATCTGTTCTCAGAAACCA TAA

Protein sequence of VB1006 (Homod imeric construct accord ing to the invention, SEQ ID NO : 13) : Am ino acid sequence, 340 amino acids .

MQVSTAALAVLLCTMALCNQVLSAPLAADTPTACCFSYTSRQIPQNFIAD YFETSSQCSKPSVIFLTKRGRQVCADPSEEWVQKYVSDLELSAELKTPLG DTTHTEPKSCDTPPPCPRCPGGGSSGGGSGGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKL TVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPGKGLGGLMHGDTPTL HEYMLDLQPETTDLYGYGQLNDSSEEEDEIDGPAGQAEPDRAHYNIVTFC CKCDSTLRLCVQSTHVDIRTLEDLLMGTLGIVCPICSQKP*

DNA seq uence of VB1007 (SEQ ID NO : 14) :

ATGCAGGTCTCCACTGCTGCCCTTGCCGTCCTCCTCTGCACCATGGCTCTCTGCAACCAGGTCCTCTCT | GCACCACTT GCTGCTGACACGCCGACCGCCTGCTGCTTCAGCTACACCTCCCGACAGATTCCACAGAATTTCATAGCTGACTACTTTG AGACGAGCAGCCAGTGCTCCAAGCCCAGTGTCATCTTCCTAACCAAGAGAGGCCGGCAGGTCTGTGCTGACCCCAGTGA GGAGTGGGTCCAGAAATACGTCAGTGACCTGGAGCTGAGTGCC | GAGCTCAAAACCCCACTTGGTGACACAACTCACAC A I GAGCCCAAATCTTGTGACACACCTCCCCCGTGCCCAAGGTGCCCA | GGCGGTGGAAGCAGCGGAGGTGGAAGTGGA | GGACAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT GCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAGCGGGCAGCCGGAGAACAACTACAACAC CACGCCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAG GGGAACATCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCGCTTCACGCAGAAGAGCCTCTCCCTGTCTCCGG GTAAA I GGCCTCGGTGGCCTG | ATGCATGGAGATACACCTACATTGCATGAATATATGTTAGATTTGCAACCAGAGACA ACTGATCTCTACGGATATGGACAATTAAATGACAGCTCAGAGGAGGAGGATGAAATAGATGGTCCAGCTGGACAAGCAG AACCGGACAGAGCCCATTACAATATTGTAACCTTTGGATGCAAGGGAGACTCTACGCTTCGGTTGTGCGTACAAAGCAC ACACGTAGACATTCGTACTTTGGAAGACCTGTTAATGGGCACACTAGGAATTGTGTGCCCCATCTGTTCTCAGAAACCA TAA

Protein sequence of VB1007 (Homod imeric construct accord ing to the invention, SEQ ID NO : 15) : Am ino acid sequence, 340 amino acids .

MQVSTAALAVLLCTMALCNQVLSAPLAADTPTACCFSYTSRQIPQNFIAD YFETSSQCSKPSVIFLTKRGRQVCADPSEEWVQKYVSDLELSAELKTPLG

DTTHTEPKSCDTPPPCPRCPGGGSSGGGSGGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKL TVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPGKGLGGLMHGDTPTL HEYMLDLQPETTDLYGYGQLNDSSEEEDEIDGPAGQAEPDRAHYNIVTFG CKGDSTLRLCVQSTHVDIRTLEDLLMGTLGIVCPICSQKP*

DNA sequence of VB1008 (SEQ ID NO : 16) :

ATGCAGGTCTCCACTGCTGCCCTTGCCGTCCTCCTCTGCACCATGGCTCTCTGCAACCAGGTCCTCTCT | GCACCACTT GCTGCTGACACGCCGACCGCCTGCTGCTTCAGCTACACCTCCCGACAGATTCCACAGAATTTCATAGCTGACTACTTTG AGACGAGCAGCCAGTGCTCCAAGCCCAGTGTCATCTTCCTAACCAAGAGAGGCCGGCAGGTCTGTGCTGACCCCAGTGA GGAGTGGGTCCAGAAATACGTCAGTGACCTGGAGCTGAGTGCC | GAGCTCAAAACCCCACTTGGTGACACAACTCACAC A I GAGCCCAAATCTTGTGACACACCTCCCCCGTGCCCAAGGTGCCCA | GGCGGTGGAAGCAGCGGAGGTGGAAGTGGA | GGACAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT GCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAGCGGGCAGCCGGAGAACAACTACAACAC CACGCCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAG GGGAACATCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCGCTTCACGCAGAAGAGCCTCTCCCTGTCTCCGG GTAAA I GGCCTCGGTGGCCTG | ATGCATGGAGATACACCTACATTGCATGAATATATGTTAGATTTGCAACCAGAGACA ACTGATCTCTACGGATATGGACAATTAAATGACAGCTCAGAGGAGGAGGATGAAATAGATGGTCCAGCTGGACAAGCAG AACCGGACAGAGCCCATTACAATATTGTAACCTTTTGTTGCAAGTGTGACTCTACGCTTCGGTTGTGCGTACAAAGCAC ACACGTAGACATTCGTACTTTGGAAGACCTGTTAATGGGCACACTAGGAATTGTGGGACCCATCGGATCTCAGAAACCA TAA

Protein sequence of VB1008 (Homod imeric construct accord ing to the invention, SEQ ID NO : 17) : Amino acid sequence, 340 amino acids.

MQVSTAALAVLLCTMALCNQVLSAPLAADTPTACCFSYTSRQIPQNFIAD

YFETSSQCSKPSVIFLTKRGRQVCADPSEEWVQKYVSDLELSAELKTPLG

DTTHTEPKSCDTPPPCPRCPGGGSSGGGSGGQPREPQVYTLPPSREEMTK

NQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKL

TVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPGKGLGGLMHGDTPTL HEYMLDLQPETTDLYGYGQLNDSSEEEDEIDGPAGQAEPDRAHYNIVTFC

CKCDSTLRLCVQSTHVDIRTLEDLLMGTLGIVGPIGSQKP*

Constructs with E6 and E7:

For the purpose of illustration only, the d ifferent domains of the constructs are separated by an " I " with the domains in the following order: Sig nal peptide | human ΜΙΡ-Ια | Hinge hi I H inge h4 | Gly-Ser Linker or Gly-Leu linker | hCH3 IgG3 | Gly-Ser Linker or Gly-Leu

I i n ke r | E7 mutant | Gly-Ser Linker or Gly-Leu I i n ke r | E6 mutant. Amino acids or nucleotides in bold illustrates sites of mutations. DNA sequence of VB1009 (SEQ ID NO : 18) :

ATGCAGGTCTCCACTGCTGCCCTTGCCGTCCTCCTCTGCACCATGGCTCTCTGCAACCAGGTCCTCTCT | GCACCACTT GCTGCTGACACGCCGACCGCCTGCTGCTTCAGCTACACCTCCCGACAGATTCCACAGAATTTCATAGCTGACTACTTTG AGACGAGCAGCCAGTGCTCCAAGCCCAGTGTCATCTTCCTAACCAAGAGAGGCCGGCAGGTCTGTGCTGACCCCAGTGA GGAGTGGGTCCAGAAATACGTCAGTGACCTGGAGCTGAGTGCC | GAGCTCAAAACCCCACTTGGTGACACAACTCACAC A I GAGCCCAAATCTTGTGACACACCTCCCCCGTGCCCAAGGTGCCCA | GGCGGTGGAAGCAGCGGAGGTGGAAGTGGA | GGACAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT GCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAGCGGGCAGCCGGAGAACAACTACAACAC CACGCCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAG GGGAACATCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCGCTTCACGCAGAAGAGCCTCTCCCTGTCTCCGG GTAAA I GGCCTCGGTGGCCTG | ATGCATGGAGATACACCTACATTGCATGAATATATGTTAGATTTGCAACCAGAGACA ACTGATCTCTACGGATATGGACAATTAAATGACAGCTCAGAGGAGGAGGATGAAATAGATGGTCCAGCTGGACAAGCAG AACCGGACAGAGCCCATTACAATATTGTAACCTTTTGTTGCAAGTGTGACTCTACGCTTCGGTTGTGCGTACAAAGCAC ACACGTAGACATTCGTACTTTGGAAGACCTGTTAATGGGCACACTAGGAATTGTGTGCCCCATCTGTTCTCAGAAACCA I GGCGGTGGAAGCAGCGGAGGTGGAAGTGGA | ATGTTTCAGGACCCACAGGAGCGACCCAGAAAGTTACCACAGTTATG CACAGAGCTGCAAACAACTATACATGATATAATATTAGAATGTGTGTACTGCAAGCAACAGTTACTGCGACGTGAGGTA TATGACTTTGCTCGACGGGATTTATGCATAGTATATAGAGATGGGAATCCATATGCTGTACGAGATAAATGTTTAAAGT TTTATTCTAAAATTAGTGAGTATAGACATTATTGTTATAGTTTGTATGGAACAACATTAGAACAGCAATACAACAAACC GTTGTGTGATTTGTTAATTAGGTGTATTAACCGACAAAAGCCACTGTGTCCTGAAGAAAAGCAAAGACATCTGGACAAA AAGCAAAGATTCCATAATATAAGGGGTCGGTGGACCGGTCGATGTATGTCTTGTTGCAGATCATCAAGAACACGTAGAG AAACCCAGCTGTAA Protein sequence of VB1009 (Homod imeric construct accord ing to the invention, SEQ ID NO : 19) : Am ino acid sequence, 501 amino acids .

MQVSTAALAVLLCTMALCNQVLS | APLAADTPTACCFSYTSRQIPQNFIAD

YFETSSQCSKPSVIFLTKRGRQVCADPSEEWVQKYVSDLELSA | ELKTPLG

DTTHT I EPKSCDTPPPCPRCP | GGGSSGGGSG | GQPREPQVYTLPPSREEMTK

NQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKL

TVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPGK | GLGGL | MHGDTPTL

HEYMLDLQPETTDLYGYGQLNDSSEEEDEIDGPAGQAEPDRAHYNIVTFC

CKCDSTLRLCVQSTHVDIRTLEDLLMGTLGIVCPICSQKP | GGGSSGGGSG |

MFQDPQERPRKLPQLCTELQTTIHDI ILECVYCKQQLLRREVYDFARRDL CIVYRDGNPYAVRDKCLKFYSKISEYRHYCYSLYGTTLEQQYNKPLCDLL

IRCINRQKPLCPEEKQRHLDKKQRFHNIRGRWTGRCMSCCRSSRTRRETQ

L*

DNA seq uence of VB1016 (SEQ ID NO : 20) :

ATGCAGGTCTCCACTGCTGCCCTTGCCGTCCTCCTCTGCACCATGGCTCTCTGCAACCAGGTCCTCTCT | GCACCACTT GCTGCTGACACGCCGACCGCCTGCTGCTTCAGCTACACCTCCCGACAGATTCCACAGAATTTCATAGCTGACTACTTTG AGACGAGCAGCCAGTGCTCCAAGCCCAGTGTCATCTTCCTAACCAAGAGAGGCCGGCAGGTCTGTGCTGACCCCAGTGA GGAGTGGGTCCAGAAATACGTCAGTGACCTGGAGCTGAGTGCC | GAGCTCAAAACCCCACTTGGTGACACAACTCACAC A I GAGCCCAAATCTTGTGACACACCTCCCCCGTGCCCAAGGTGCCCA | GGCGGTGGAAGCAGCGGAGGTGGAAGTGGA | GGACAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT GCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAGCGGGCAGCCGGAGAACAACTACAACAC CACGCCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAG GGGAACATCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCGCTTCACGCAGAAGAGCCTCTCCCTGTCTCCGG GTAAA I GGCCTCGGTGGCCTG | ATGCATGGAGATACACCTACATTGCATGAATATATGTTAGATTTGCAACCAGAGACA ACTGATCTCTACGGATATGGACAATTAAATGACAGCTCAGAGGAGGAGGATGAAATAGATGGTCCAGCTGGACAAGCAG AACCGGACAGAGCCCATTACAATATTGTAACCTTTTGTTGCAAGTGTGACTCTACGCTTCGGTTGTGCGTACAAAGCAC ACACGTAGACATTCGTACTTTGGAAGACCTGTTAATGGGCACACTAGGAATTGTGTGCCCCATCTGTTCTCAGAAACCA I GGCGGTGGAAGCAGCGGAGGTGGAAGTGGA | ATGTTTCAGGACCCACAGGAGCGACCCAGAAAGTTACCACAGTTATG CACAGAGCTGCAAACAACTATACATGATATAATATTAGAATGTGTGTACTGCAAGCAACAGTTACTGCGACGTGAGGTA TATGACTTTGCTTTTCGGGATTTATGCATAGTATATAGAGATGGGAATCCATATGCTGTACGAGATAAATGTTTAAAGT TTTATTCTAAAATTAGTGAGTATAGACATTATTGTTATAGTTTGTATGGAACAACATTAGAACAGCAATACAACAAACC GTTGTGTGATTTGTTAATTAGGTGTATTAACCGACAAAAGCCACTGTGTCCTGAAGAAAAGCAAAGACATCTGGACAAA AAGCAAAGATTCCATAATATAAGGGGTCGGTGGACCGGTCGATGTATGTCTTGTTGCAGATCATCAAGAACACGTAGAG AAACCCAGCTGTAA

Protein sequence of VB1016 (Homod imeric construct accord ing to the invention, SEQ ID NO : 21) : Am ino acid sequence, 501 amino acids

MQVSTAALAVLLCTMALCNQVLSAPLAADTPTACCFSYTSRQIPQNFIAD

YFETSSQCSKPSVIFLTKRGRQVCADPSEEWVQKYVSDLELSAELKTPLG DTTHTEPKSCDTPPPCPRCPGGGSSGGGSGGQPREPQVYTLPPSREEMTK

NQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKL

TVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPGKGLGGLMHGDTPTL

HEYMLDLQPETTDLYGYGQLNDSSEEEDEIDGPAGQAEPDRAHYNIVTFC

CKCDSTLRLCVQSTHVDIRTLEDLLMGTLGIVCPICSQKPGGGSSGGGSG MFQDPQERPRKLPQLCTELQTTIHDI ILECVYCKQQLLRREVYDFAFRDL

CIVYRDGNPYAVRDKCLKFYSKISEYRHYCYSLYGTTLEQQYNKPLCDLL

IRCINRQKPLCPEEKQRHLDKKQRFHNIRGRWTGRCMSCCRSSRTRRETQ

L* SEQ ID NO:22:

>tr|Q778I6|Q778I6_HPV16 E6 protein OS=Human papillomavirus type 16 GN = E6 PE=4 SV=1; (Underlined amino acids denotes amino acids that may be deleted; Potential amino acids that may be mutated are highlighted)

MFQDPQERPRKLPQLCTELQTTIHDIILECVYCKQQLLRREVYDFAFRDLCIVYRDGNPYAVCDKCLKFYS KISEYRHYCYSLYGTTLEQQYNKPLCDLLIRCINCQKPLCPEEKQRHLDKKQRFHNIRGRWTG RCMSCCR SSRTRRETQL SEQID NO:23:

>sp|P03129|VE7_HPV16 Protein E7 OS=Human papillomavirus type 16 GN = E7 PE=1 SV=1; (Underlined amino acids denotes amino acids that may be deleted; Potential amino acids that may be mutated are highlighted)

MHGDTPTLHEYMLDLQPETTDLYCYEQLNDSSEEEDEIDGPAGQAEPDRAHYNIVTFCCKCDSTLRLCVQ STHVDIRTLEDLLMGTLGIVCPICSQKP

SEQ ID NO:24:

>sp|P06463|VE6_HPV18 Protein E6 OS=Human papillomavirus type 18 GN = E6 PE=1 SV=1 MARFEDPTRRPYKLPDLCTELNTSLQDIEITCVYCKTVLELTEVFEFAFKDLFVVYRDSI PHAACHKCIDFYSRIRELRHYSDSVYG DTLEKLTNTGLYNLLIRCLRCQKPLNPAEKLRH LNEKRRFHNIAGHYRGQCHSCCNRARQERLQRRRETQV

SEQ ID NO:25:

>sp|P06788|VE7_HPV18 Protein E7 OS=Human papillomavirus type 18 GN = E7 PE=3 SV=2 MHGPKATLQDIVLHLEPQNEIPVDLLCHEQLSDSEEENDEIDGVNHQHLPARRAEPQRHT MLCMCCKCEARIKLVVESSADDLRAFQQLFLNTLSFVCPWCASQQ

SEQ ID NO:26:

Hinge regions (IgG3 UH hinge), 12 amino acids: ELKTPLGDTTHT

SEQ ID NO:27:

Hinge region (IgG3, MH hinge, 15 amino acids): EPKSCDTPPPCPRCP

SEQ ID NO:28:

Gly-Ser Linker: GGGSSGGGSG

SEQ ID NO:29: hCH3 IgG3:

GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKL TVDKSRWQQG NIFSCSVM H EALH N RFTQKSLSLSPGK

SEQ ID NO:30: Linker: GLGGL

SEQ ID NO:31: DNA sequence of VB1020: ATGCAGGTCTCCACTGCTGCCCTTGCCGTCCTCCTCTGCACCATGGCTCTCTGCAACCAGGTCCTCTCT | GCACCACTT GCTGCTGACACGCCGACCGCCTGCTGCTTCAGCTACACCTCCCGACAGATTCCACAGAATTTCATAGCTGACTACTTTG AGACGAGCAGCCAGTGCTCCAAGCCCAGTGTCATCTTCCTAACCAAGAGAGGCCGGCAGGTCTGTGCTGACCCCAGTGA GGAGTGGGTCCAGAAATACGTCAGTGACCTGGAGCTGAGTGCC | GAGCTCAAAACCCCACTTGGTGACACAACTCACAC A I GAGCCCAAATCTTGTGACACACCTCCCCCGTGCCCAAGGTGCCCA | GGCGGTGGAAGCAGCGGAGGTGGAAGTGGA | GGACAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT GCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAGCGGGCAGCCGGAGAACAACTACAACAC CACGCCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAG GGGAACATCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCGCTTCACGCAGAAGAGCCTCTCCCTGTCTCCGG

GTAAA| GGCCTCGGTGGCCTG/ATGCATGGCGATACCCCAACACTCCATGAGTACATGCTGGACCTTCAGCCCGAGAC TACGGATCTGTATGGCTATGGGCAGTTGAATGACTCATCTGAGGAGGAGGACGAAATAGACGGCCCAGCTGGTCAAGCC GAACCGGATAGAGCCCACTACAACATTGTGACCTTTTGCTGTAAGTGTGACAGCACTCTGAGACTGTGTGTTCAGTCCA CTCATGTCGACATACGCACATTGGAGGATCTCCTGATGGGAACACTGGGAATTGTGTGTCCCATCTGTTCCCAAAAGCC

T/GGAGGTGGAAGCAGTGGAGGCGGTTCAGGC/ATGTTCCAAGATCCTCAAGAACGTCCTCGTAAGCTGCCACAGCTGT GTACCGAGCTTCAGACCACCATTCACGACATCATCCTGGAGTGCGTCTATTGCAAACAGCAGCTCCTTAGAAGGGAAGT GTACGATTTTGCACGGAGGGACCTCTGCATCGTGTATCGGGACGGCAATCCCTATGCGGTACGGGATAAATGCCTGAAG TTCTACAGCAAAATCTCCGAGTACCGGCACTACTGCTACTCTCTCTATGGGACGACTCTGGAACAGCAGTACAACAAGC CCTTGTGCGATCTGCTGATTCGCTGCATTAATCGCCAGAAACCTCTGTGCCCAGAAGAGAAGCAAAGACACCTGGACAA GAAACAGCGATTCCACAACATCCGAGGGAGATGGACAGGGAGGTGTATGAGCTGCTGTCGGAGTTCTAGGACAAGGCGC GAAACCCAGCTTTGA

SEQ ID NO : 32 : Protein sequence of VB1020 (Homod imeric construct according to the invention Amino acid sequence, 501 amino acids : MQVSTAALAVLLCTMALCNQVLS | APLAADTPTACCFSYTSRQIPQNFIAD

YFETSSQCSKPSVIFLTKRGRQVCADPSEEWVQKYVSDLELSA | ELKTPLG

DTTHT I EPKSCDTPPPCPRCP | GGGSSGGGSG | GQPREPQVYTLPPSREEMTK

HEYMLDLQPETTDLYGYGQLNDSSEEEDEIDGPAGQAEPDRAHYNIVTFC

CKCDSTLRLCVQSTHVDIRTLEDLLMGTLGIVCPICSQKP | GGGSSGGGSG |

MFQDPQERPRKLPQLCTELQTTIHDI ILECVYCKQQLLRREVYDFARRDL CIVYRDGNPYAVRDKCLKFYSKISEYRHYCYSLYGTTLEQQYNKPLCDLL IRCINRQKPLCPEEKQRHLDKKQRFHNIRGRWTGRCMSCCRSSRTRRETQ

L*

SEQ ID NO : 33 : DNA sequence of VB1021 :

ATGCAGGTCTCCACTGCTGCCCTTGCCGTCCTCCTCTGCACCATGGCTCTCTGCAACCAGGTCCTCTCT | GCACCACTT GCTGCTGACACGCCGACCGCCTGCTGCTTCAGCTACACCTCCCGACAGATTCCACAGAATTTCATAGCTGACTACTTTG AGACGAGCAGCCAGTGCTCCAAGCCCAGTGTCATCTTCCTAACCAAGAGAGGCCGGCAGGTCTGTGCTGACCCCAGTGA GGAGTGGGTCCAGAAATACGTCAGTGACCTGGAGCTGAGTGCC | GAGCTCAAAACCCCACTTGGTGACACAACTCACAC A I GAGCCCAAATCTTGTGACACACCTCCCCCGTGCCCAAGGTGCCCA | GGCGGTGGAAGCAGCGGAGGTGGAAGTGGA | GGACAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT GCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAGCGGGCAGCCGGAGAACAACTACAACAC CACGCCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAG GGGAACATCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCGCTTCACGCAGAAGAGCCTCTCCCTGTCTCCGG GTAAA/GGCCTCGGTGGCCTG/ATGCATGGTGACACACCAACCCTGCACGAATACATGCTCGATCTGCAGCCAGAG ACTACCGACCTTTACGGCTATGGGCAGTTGAACGACAGCTCTGAGGAGGAGGACGAGATCGATGGTCCTGCTGGA CAAGCAGAACCAGACAGAGCCCACTACAACATCGTAACCTTTTGCTGCAAGTGTGACAGTACCCTTCGTTTGTGCG TTCAGAGCACGCATGTCGACATTCGGACACTGGAGGATCTGCTCATGGGGACTCTGGGGATTGTGTGTCCTATTTG CAGCCAGAAACCA/GGCGGAGGATCTTCAGGAGGCGGGAGTGGC/ATGTTCCAAGACCCTCAGGAACGCCCTCGG AAACTGCCCCAATTGTGTACTGAGCTCCAGACAACGATACACGACATAATCCTGGAGTGCGTGTATTGCAAGCAGC AGCTTCTGAGGAGGGAAGTGTACGATTTTGCCAGGAGAGATGGCTGCATTGTCTACCGAGATGGCAATCCCTATG CGGTGTGTGATAAGTGTCTGAAGTTCTATTCCAAAATCAGCGAATATCGGCATTATTGCTACTCACTGTACGGAACT ACCCTCGAACAGCAGTACAACAAACCGCTCTGTGATCTGCTGATCAGATGCATCAATCGGCAGAAACCCCTTTGTC CCGAAGAGAAGCAAAGACACCTGGACAAGAAGCAGAGGTTCCACAATACCCGAGGTCGTTGGACTGGGCGCTGC ATGTCCTGTTGTCGCTCCTCTCGCACAAGGAGAGAGACACAACTGTGA SEQ ID NO : 34 : Protein sequence of VB1021 (Homod imeric construct according to the invention. Amino acid sequence, 501 amino acids :

MQVSTAALAVLLCTMALCNQVLS | APLAADTPTACCFSYTSRQIPQNFIAD

YFETSSQCSKPSVIFLTKRGRQVCADPSEEWVQKYVSDLELSA | ELKTPLG

DTTHT I EPKSCDTPPPCPRCP | GGGSSGGGSG | GQPREPQVYTLPPSREEMTK

NQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKL

TVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPGK | GLGGL | MHGDTPTL

HEYMLDLQPETTDLYGYGQLNDSSEEEDEIDGPAGQAEPDRAHYNIVTFC

CKCDSTLRLCVQSTHVDIRTLEDLLMGTLGIVCPICSQKP | GGGSSGGGSG |

MFQDPQERPRKLPQLCTELQTTIHDI ILECVYCKQQLLRREVYDFARRDG

CIVYRDGNPYAVCDKCLKFYSKISEYRHYCYSLYGTTLEQQYNKPLCDLL

IRCINRQKPLCPEEKQRHLDKKQRFHNTRGRWTGRCMSCCRSSRTRRETQ

L*

Claims

1. A homod imeric protein of two identical amino acid chains, each amino acid chain comprising (1) a signal peptide, (2) a targeting unit, (3) a d imerization motif, and (4) an antigenic unit, said targeting unit comprising an amino acid sequence having at least 80 % sequence identity to the amino acid sequence 24-93 of SEQ ID NO : l, and an antigenic unit comprising an amino acid sequence of human papillomavirus (H PV), such as an antigenic unit comprising an amino acid sequence of H PV16 and/or HPV18, such as an antigenic unit derived from early proteins E6 and/or E7 of H PV16 and/or H PV18.

2. The homod imeric protein accord ing to claim 1, wherein said targeting unit, d imerization motif and antigenic unit in said amino acid chain are in the N-terminal to C- terminal order of targeting unit, d imerization motif and antigenic unit.

3. The homod imeric protein accord ing to any one of claims 1 or 2, wherein said sig nal peptide consists of an amino acid sequence having at least 80 % sequence identity to the amino acid sequence 1-23 of SEQ ID NO : l .

4. The homod imeric protein accord ing to claim 3, wherein said signal peptide consists of an amino acid sequence having at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99%, such as 100% sequence identity to the amino acid sequence 1-23 of SEQ ID NO : l .

5. The homod imeric protein accord ing to any one of claims 1-4, wherein said targeting unit consists of an amino acid sequence having at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% sequence identity to the amino acid sequence 24-93 of SEQ ID NO : l .

6. The homod imeric protein accord ing to any one of claims 1-5, wherein the d imerization motif comprises a hinge reg ion and optionally another domain that facilitate d imerization, such as an immu nog lobulin domain, optionally connected throug h a linker.

7. The homod imeric protein accord ing to claim 6, wherein the hinge region is Ig derived, such as derived from IgG3.

8. The homod imeric protein accord ing to any one of claims 6-7, wherein the hinge reg ion has the ability to form one, two, or several covalent bonds.

9. The homod imeric protein accord ing to claim 8, wherein the covalent bond is a d isulphide bridge.

10. The homod imeric protein accord ing to any one of claims 6-9, wherein the

immunog lobulin domain of the dimerization motif is a carboxyterminal C domain, or a sequence that is substantially identical to said C domain or a variant thereof.

11. The homod imeric protein accord ing to claim 10, wherein the carboxyterminal C domain is derived from IgG.

12. The homod imeric protein accord ing to any one of claims 6-11, wherein the immunog lobulin domain of the dimerization motif has the ability to homodimerize.

13. The homod imeric protein accord ing to any one of claims 6-12, wherein said immunog lobulin domain has the ability to homod imerize via noncovalent interactions.

14. The homod imeric protein accord ing to claim 13, wherein said noncovalent interactions are hydrophobic interactions.

15. The homod imeric protein accord ing to any one of claims 1-14, wherein said d imerization domain does not comprise the CH2 domain.

16. The homod imeric protein accord ing to any one of claims 1-15, wherein the d imerization motif consist of hinge exons h i and h4 connected throug h a linker to a C_H3 domain of human IgG3.

17. The homod imeric protein accord ing to any one of claims 1-16, wherein the d imerization motif consist of an amino acid sequence having at least 80 % sequence identity to the amino acid sequence 94-237 of SEQ ID NO : 3.

18. The homod imeric protein accord ing to any one of claims 2-17, wherein said linker is a G3S2G3SG linker.

19. The homod imeric protein accord ing to any one of claims 1-18, wherein said antigenic unit and the d imerization motif is connected through a linker, such as a GLGGL linker or a GLSGL linker.

20. The homod imeric protein accord ing to any one of claims 1-19, wherein said targeting unit consists of amino acids 24-93 of SEQ ID NO : l, or a variant thereof.

21. The homod imeric protein accord ing to any one of claims 1-20, which homodimeric protein have increased affinity for any one chemokine receptor selected from CCR1, CCR3 and CCR5 as compared to the affinity of the same homodimeric protein with the targeting unit consisting of amino acids 24-93 of SEQ ID NO : l, or a variant thereof.

22. The homod imeric protein accord ing to any one of claims 1-21, wherein said antigenic unit comprises an amino acid sequence having at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% sequence identity to the amino acid sequence 243-293 of SEQ ID NO : 3.

23. The homod imeric protein accord ing to any one of claims 1-22, wherein said antigenic unit consists of an amino acid sequence having at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% sequence identity to the amino acid sequence 243-293 of SEQ ID NO : 3.

24. The homod imeric protein accord ing to 22 or 23, wherein said antigenic unit comprises one or more amino acid substitutions at a position selected from the list consisting of F47, L50, C63, C106 and 1128 of SEQ ID NO : 22, or a deletion involving one or more amino acid selected from the list consisting of Y43-L50 of SEQ ID NO : 22.

25. The homod imeric protein accord ing to any one of claims 1-23, wherein said antigenic unit comprises the amino acid sequence 243-293 of SEQ ID NO : 3, SEQ ID NO : 5, SEQ ID NO : 7, or SEQ ID NO :9, or a variant or antigenic fragment thereof.

26. The homod imeric protein accord ing to any one of claims 1-23, wherein said antigenic unit consists of the amino acid sequence 243-293 of SEQ ID NO : 3, SEQ ID NO : 5, SEQ ID NO : 7, or SEQ ID NO :9, or a variant or antigenic fragment thereof.

27. The homod imeric protein accord ing to any one of claims 1-21, wherein said antigenic unit comprises an amino acid sequence having at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% sequence identity to the amino acid sequence 243-340 of SEQ ID NO : l l .

28. The homod imeric protein accord ing to any one of claims 1-21, wherein said antigenic unit consists of an amino acid sequence having at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% sequence identity to the amino acid sequence 243-340 of SEQ ID NO : l l .

29. The homod imeric protein accord ing to claims 27 or 28, wherein said antigenic unit comprises one or more amino acid substitutions at a position selected from the list consisting of C24, E26, C58, C61, C91, and C94 of SEQ ID NO : 23, or a deletion involving one or more amino acid selected from the list consisting of L22-E26 and/or C58-C61 and/or C91-S95 of SEQ ID NO : 23.

30. The homod imeric protein accord ing to any one of claims 1-21, wherein said antigenic unit comprises the amino acid sequence 243-340 of SEQ ID NO : l l, SEQ ID NO : 13, SEQ ID NO : 15, or SEQ ID NO : 17, or a variant or antigenic fragment thereof.

31. The homod imeric protein accord ing to any one of claims 1-21, wherein said antigenic unit consists of the amino acid sequence 243-340 of SEQ ID NO : l l, SEQ ID NO : 13, SEQ ID NO : 15, or SEQ ID NO : 17, or a variant or antigenic fragment thereof.

32. The homod imeric protein accord ing to any one of claims 1-21, wherein said antigenic unit comprises an amino acid sequence having at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% sequence identity to the amino acid sequence 243-501 of SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:32, or SEQ ID NO:34.

33. The homodimeric protein according to any one of claims 1-21, wherein said antigenic unit consists of an amino acid sequence having at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% sequence identity to the amino acid sequence 243-501 of SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:32, or SEQ ID NO:34.

34. The homodimeric protein according to any one of claims 1-22, 24-25, 27, 29-30, 32- 33, wherein said antigenic unit comprising an amino acid sequence of human papillomavirus

16 (HPV16) derived from both early proteins E6 and E7.

35. The homodimeric protein according to claims 32-34, wherein said antigenic unit comprises one or more amino acid substitutions at a position selected from the list consisting of F47, L50, C63, C106 and 1128 of SEQ ID NO:22 and C24, E26, C58, C61, C91, C94 of SEQ ID NO:23.

36. The homodimeric protein according to any one of claims 1-21, wherein said antigenic unit consists of the amino acid sequence 243-501 of SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:32, or SEQ ID NO:34, or a variant or antigenic fragment thereof.

37. The homodimeric protein according to any one of claims 1-21, wherein said amino acid chain consists of an amino acid sequence selected from the list consisting of SEQ ID

NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:ll, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:32, and SEQ ID NO:34, or a variant or antigenic fragment thereof.

38. The homodimeric protein according to any one of claims 1-21, wherein said antigenic unit comprises an amino acid sequence having at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% sequence identity to any one amino acid sequence selected from SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, and SEQ ID NO:25.

39. The homodimeric protein according to any one of claims 1-21, wherein said antigenic unit consist of an amino acid sequence having at least 80%, such as at least 81%, such as at least 82%, such as at least 83%, such as at least 84%, such as at least 85%, such as at least 86%, such as at least 87%, such as at least 88%, such as at least 89%, such as at least 90%, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, such as at least 99% sequence identity to any one amino acid sequence selected from SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, and SEQ ID NO:25.

40. The homodimeric protein according to any one of claims 1-39, in its mature form without any signal peptide sequence.

41. An amino acid chain comprising (1) a signal peptide, (2) a targeting unit, (3) a dimerization motif, and (4) an antigenic unit, said targeting unit comprising an amino acid sequence having at least 80 % sequence identity to the amino acid sequence 24-93 of SEQ ID NO:l, and an antigenic unit comprising an amino acid sequence of human papillomavirus (HPV), such as an antigenic unit comprising an amino acid sequence of HPV16 and/or HPV18, such as an antigenic unit derived from early proteins E6 and/or E7 of HPV16 and/or HPV18, which amino acid chain is able to form a homodimeric protein according to any one of clams 1-40.

42. A nucleic acid molecule, such as a DNA, encoding the amino acid chain according to claim 41.

43. The nucleic acid molecule according to claim 42, which nucleic acid molecule is human codon optimized.

44. A nucleic acid molecule comprising any one of nucleotide sequences selected from the list consisting of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:31 and SEQ ID NO:33, or a variant thereof.

45. The nucleic acid molecule according to claims 42-44 comprised by a vector.

46. The nucleic acid molecu le accord ing to any one of claims 42-45 formulated for administration to a patient to induce production of the homod imeric protein in said patient.

47. The homod imeric protein accord ing to any one of claims 1-40, or an amino acid chain accord ing to claim 41, or the nucleic acid molecule accord ing to any one of claims 42-46 for use as a med icament.

48. A pharmaceutical composition comprising the homodimeric protein accord ing to any one of claims 1-40, or an amino acid chain according to claim 41, or the nucleic acid molecu le accord ing to any one of claims 42-46.

49. A host cell comprising the nucleic acid molecule according to any one of claims 42-46.

50. A method for preparing a homodimeric protein according to any one of claims 1-40, or an amino acid chain of claim 41, the method comprising a) transfecting the nucleic acid molecu le accord ing to any one of claims 41-45 into a cell popu lation;

b) culturing the cell population;

c) collecting and purifying the homodimeric protein, or amino acid chain expressed from the cell population.

51. A method for preparing a vaccine, such as a DNA vaccine, comprising an

immunolog ically effective amount of a nucleic acid molecu le accord ing to any one of claims 42-46, the method comprising a) preparing a nucleic acid molecule accord ing to any one of claims 41-45; b) d issolving the nucleic acid molecu le obta ined under step a) in a

pharmaceutically acceptable carrier, d iluent, or buffer.

52. A vaccine against H PV comprising an immunolog ically effective amou nt of a homodimeric protein according to any one of claims 1-40, or an amino acid chain accord ing to claim 41, or nucleic acid molecule, such as a DNA, accord ing to any one of claims 42-46, wherein said vaccine is able to trigger both a T-cell- and B-cell immune response.

53. The vaccine accord ing to claim 52 further comprising a pharmaceutically acceptable carrier and/or adjuvant.

54. A method of treating or preventing a HPV induced d isease or cond ition, such as a cancer or an infectious disease caused by H PV in a patient, the method comprising administering to the patient in need thereof, a homodimeric protein accord ing to any one of claims 1-40, or an amino acid chain accord ing to claim 41, or the nucleic acid molecu le, such as a DNA, accord ing to one of claims 42-46.

55. The method accord ing to claim 54, wherein the method comprises administering to the patient in need thereof of a nucleic acid molecule, such as a DNA, accord ing to one of claims 42-46 with a subsequent step of electroporation.

56. The method accord ing to claims 54 or 55, wherein the administration is performed intra dermal or intra muscular.