Antibodies to peptides that target GIT receptors and related methods

Abstract

The invention provides an antibody or antibody fragment specific to a domain of a GIT targeting agent, such as a polyclonal antibody, monoclonal antibody, chimeric antibody, single chain antibody, a Fab fragment or a Fab expression library. In particular, the invention provides an antibody or antibody fragment, wherein the GIT targeting agent is selected from the group consisting of ZElan033 (PAX2 15 mer), ZElan088 (HAX42-2 20 mer) or ZElan053 (P31 D-form 16 mer). Numerous methods using these GIT targeting agent specific antibodies are disclosed.

Description

FIELD OF THE INVENTION

The present invention relates to antibodies to random peptides capable of targeting or specifically binding to gastrointestinal tract (GIT) transport receptors. In particular, this invention relates to methods of using these antibodies as well as specific antibody preparations directed to particular GIT random peptide targeting agents.

BACKGROUND OF THE INVENTION

Antibodies can be produced by using an immunogen to generate antibodies which immunospecifically bind such an immunogen. Such antibodies include but are not limited to polyclonal, monoclonal, chimeric, single chain, Fab fragments, and an Fab expression library.

Various procedures known in the art may be useful for the production of polyclonal antibodies to an immunogen. For the production of antibody, various host animals, such as rabbits, mice, rats, fowl etc. can be immunized by injection with the immunogen. Various adjuvants may be used to increase the immunological response, depending on the host species, such as Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanins, dinitrophenol, and potentially useful human adjuvants such as BCG (bacille Calmette-Guerin) and corynebacterium parvum.

As disclosed and claimed in WO 98/51325, which reference is hereby incorporated by reference in its entirety, we have identified random peptides and their fragments, motifs, derivatives, analogs or peptidomimetics thereof which are capable of specific binding to GIT transport receptors such as the D2H, hSI, HPT1 and hPEPT1 receptors (hereinafter referred to as “GIT targeting agents”). These GIT targeting agents are capable of facilitating transport of an active agent through a human or animal gastro-intestinal tissue and have use, for example, in facilitating transport of active agents from the lumenal side of the GIT into the portal, hepatic or systemic blood system and/or in targeting active agents to the GIT. Thus, for example, by binding (covalently or noncovalently) the GIT targeting agent to an orally administered active agent, the active agent can be targeted to specific receptor sites or transport pathways which are known to operate in the human gastrointestinal tract, thus facilitating its absorption into the systemic system. Preferably, the active agent is a drug or a drug-containing nano- or microparticle. Preferably, the tissue through which transport is facilitated is of the duodenum, jejunum, ileum, ascending colon, transverse colon, descending colon, or pelvic colon. The tissue is most preferably epithelial cells lining the lumenal side of the GIT.

The GIT targeting agents are bound to a material comprising an active agent. Such compositions have use in targeting the active agent to the GIT and/or in facilitating transfer through the lumen of the GIT into the systemic circulation. Where the active agent is an imaging agent, such compositions can be administered in vivo to image the GIT (or particular transport receptors thereof). Other active agents include but are not limited to: any drug or antigen or any drug- or antigen-loaded or drug- or antigen-encapsulated nanoparticle, microparticle, liposome, or micellar formulation capable of eliciting a biological response in a human or animal. Examples of drug- or antigen-loaded or drug- or antigen-encapsulated formulations include those in which the active agent is encapsulated or loaded into nano- or microparticles, such as biodegradable nano- or microparticles, and which have GIT targeting agents adsorbed, coated or covalently bound, such as directly linked or linked via a linking moiety, onto the surface of the nano- or microparticle. Additionally, the GIT targeting agent can form the nano- or microparticle itself or the GIT targeting agent can be covalently attached to the polymer or polymers used in the production of the biodegradable nano- or microparticles or drug-loaded or drug-encapsulated nano- or microparticles or the peptide can be directly conjugated to the active agent.

The GIT targeting agent bound to the active agent can be employed in methods of treatment (and prophylaxis) by administration to a subject of an effective amount of targeting agent/active agent. Any disease or disorder of interest amenable to therapy or prophylaxis by providing a drug in vivo systemically or by targeting a drug in vivo to the GIT (by linkage to a GIT targeting agent) can be treated or prevented by this administration. Any route of administration known in the art may be used, including but not limited to oral, nasal, topical, intravenous, intraperitoneal, intradermal, mucosal, intrathecal, intramuscular, etc. Preferably, administration is oral.

However, to fully characterize the compositions as well as to determine the fate of the compositions following administration to a subject, antibodies to the specific GIT targeting agents are needed.

SUMMARY OF THE INVENTION

The present invention provides antibodies or antibody fragments specific to a domain of a GIT targeting agent, particularly antibodies to ZElan033 (PAX2 15 mer), ZElan088(HAX42-2 20 mer) and ZElan053 (P31 D-form 16 mer).

Additionally, numerous methods are provided below that employ the GIT targeting agent specific antibodies of this invention, including methods of detecting, quantitating, and locating the GIT targeting agent either in a pharmaceutical composition or after contact of a GIT targeting agent-containing composition with human or animal gastro-intestinal tissue.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the immuno responses of three groups of 2 rabbits, each group immunized, respectively, with one of KLH conjugated ZElan033, KLH conjugated ZElan088 and KLH conjugated ZElan053, when the fourth bleed samples are tested by ELISA on their respective unconjugated peptides.

FIG. 2 shows the cross reactivity of rabbit antisera for three groups of 2 rabbits, each group immunized, respectively, with one of KLH conjugated ZElan033, KLH conjugated ZElan088 and KLH conjugated ZElan053, when the fourth bleed samples are tested by ELISA on each of synthetic peptides HAX42.2, PAX 2 15 mer and P31-D-form.

FIG. 3 shows the immuno-reactivity of anti-HAX42-2 antisera (fifth bleed samples) on a variety of synthetic peptides. The sequence for Zelan021 is SEQ ID NO:4 in the Sequence Listing herein. The sequence for Zelan071 is SEQ ID NO: 5, that for Zelan088 is SEQ ID NO:2, and that for Unconj. Antigen is SEQ ID NO:6.

FIG. 4 shows the immuno-reactivity of anti-PAX2 antisera (fifth bleed samples) on a variety of synthetic peptides. The sequence for Zelan108 is SEQ ID NO:7 in the Sequence Listing herein. The sequence for Zelan104 is SEQ ID NO: 8, that for Unconj.Ag is SEQ ID NO:1, and that for Zelan103A is SEQ ID NO:9.

FIG. 5 shows the immuno-reactivity of anti-P31 D-form antisera (fifth bleed samples) on a variety of synthetic peptides. The sequence for Zelan024 is SEQ ID NO:10 in the Sequence Listing herein. The sequence for Unconj.Ag is SEQ ID NO: 3, that for Zelan054 is SEQ ID NO:11, and that for ZElan145 is SEQ ID NO:12.

DETAILED DESCRIPTION OF THE INVENTION

According to this invention, a GIT targeting agent may be used as an immunogen to generate antibodies which immunospecifically bind such an immunogen. Such antibodies include but are not limited to polyclonal, monoclonal, chimeric, single chain, Fab fragments, and a Fab expression library. Particular antibodies provided by this invention include but are not limited to antibodies or antibody fragments, preferably polyclonal antibodies or antibody fragments, specific to a domain of GIT targeting agents ZElan033 (PAX2 15 mer), ZElan088 (HAX42-2 20 mer) and ZElan053 (P31 D-form 16 mer). Additional GIT targeting agents are disclosed throughout the above-referenced WO 98/51325.

The HPT1, hPEPT1, D2H, and hSI receptors were selected for cloning as GIT receptor targets based on several criteria, including: (1) expression on surface of epithelial cells in gastro-intestinal tract (GIT); (2) expression along the length of small intestine (HPT1, hPEPT1, D2H); (3) expression locally at high concentration (hSI); (4) large putative extracellular domains facing into the lumen of the GIT; and (5) extracellular domains that permit easy access and bioadhesion by targeting particles.

The four recombinant receptor sites screened with the peptide libraries additionally have the following characteristics:

Receptor Characteristics
D2H      Transport of neutral/basic amino acids;
         a transport activating protein for a
         range of amino acid translocases
hS1      Metabolism of sucrose and other sugars,
         represents 9% of brush border membrane
         protein Jejunum
HPT1     di/tri peptide transporter or facilitator
         of peptide transport
hPEPT1   di/tri peptide transporter

The following receptor domains were cloned and expressed as His-tag fusion proteins by standard techniques:

Cloning of Extracellular Domain of Selected Receptor Site

		Domain (amino	SEQ ID
	Receptor	acid residues)	NOS
	hPEPT1 a	391-571	16
	HPT1 b	29-273	15
	hSI c	272-667	14
	D2H d	387-685	13
	a Liang et al., 1995, J. Biol. Chem. 270: 6456-6463;
	b Dantzig et al., 1994, Association of Intestinal Peptide Transport with a Protein Related to the Cadherin Superfamily;
	c Chantret et al., Biochem. J. 285: 915-923;
	d Bertran et al., J. Biol. Chem. 268: 14842-14949.

The receptor proteins were expressed as His-tag fusion proteins and affinity purified under denaturing conditions, using urea or guanidine HCI, utilizing the pET His-tag metal chelate affinity for Ni-NTA Agarose (Hochuli, E., Purification of recombinant proteins with metal chelate adsorbent, Genetic Engineering, Principals and Methods (J. K. Setlow, ed.), Plenum Press, NY, Vol. 12 (1990), pp. 87-98).

As indicated in WO 98/51325, phage which showed specificity to a GIT receptor was further characterized by ELISA on a variety of recombinant proteins. Phage which continued to exhibit GIT receptor specificity was sequenced. Their insert sequences are summarized as follows:

	SEQ.
	ID.
	NO	TARGET BINDING PHAGE INSERT SEQUENCE
hSI
S15	17.	RSGAYESPDGRGGRSYVGGGGGCGNIGRKHNLW-
		GLRTASPACWD
S21	18.	SPRSFWPWSRHESFGISNYLGCGYRTCISGTMT-
		KSSPIYPRHS
S22	19.	SSSSDWGGVPGKWRERFKGRGCGISITSVLTGK-
		PNPCPEPKAA
Sni10	20.	RVGQCTDSDVRRPWARSCAHQGCGAGTRNSHGCI-
		TRPLRQASAH
Sni28	21.	SHSGGMNRAYGDVFRELRDRWNATSHHTRPTP-
		QLPRGPN
Sni34	22.	SPCGGSWGRFMQGGLFGGRTDGCGAHRNRTSA-
		SLEPPSSDY
Sni38	23.	RGAADQRRGWSENLGLPRVGWDAIAHNSYTF-
		TSRRPRPP
Sni45	24.	SGGEVSSWGRVNDLCARVSWTGCGTARSARTD-
		NKGFLPKHSSLR
SniAX2	25.	SDSDGDHYGLRGGVRCSLRDRGCGLALSTVHA-
		GPPSFYPKLSSP
SniAX4	26.	RSLGNYGVTGTVDVTVLPMPGHANHLGVSSA-
		SSSDPPRR
SniAX6	27.	RTTTAKGCLLGSFGVLSGCSFTPTSPPPHL-
		GYPPHSVN
SniAX8	28.	SPKLSSVGVMTKVTELPTEGPNAISIPI-
		SATLGPRNPLR
D2H
DAB3	29.	RWCGAELCNSVTKKFRPGWRDHANPSTHH-
		RTPPPSQSSP
DAB7	30.	RWCGADDPCGASRWRGGNSLFGCGLRCSMQ-
		STPSGRIHSTSTS
DAB10	31.	SKSGEGGDSSRGETGWARVRSHAMTAGRFRWY-
		NQLPSDR
DAB18	32.	RSSANNCEWKSDWMRRACIARYANSSGPARAV-
		DTKAAP
DAB24	33.	SKWSWSSRWGSPQDKVEKTRAGCGGSPSSTN-
		CHPYTFAPPPQAG
DAB30	34.	SGFWEFSRGLWDGENRKSVRSGCGFRGSSAQG-
		PCPVTPATIDKH
DAX15	35.	SESGRCRSVSRWMTTWQTQKGGCGSNVSRGSP-
		LDPSHQTGHATT
DAX23	36.	REWRFAGPPLDLWAGPSLPSFNASSHPRALR-
		TYWSQRPR
DAX24	37.	RMEDIKNSGWRDSCRWGDLRPGCGSRQWYPS-
		NMRSSRDYPAGGH
DAX27	38.	SHPWYRHWNHGDFSGSGQSRHTPPESPHPGRP-
		NATI
DCX8	39.	RYKHDIGCDAGVDKKSSSVRGGCGAHSSPPRAG-
		RGPRGTMVSRL
DCX11	40.	SQGSKQCMQYRTGRLTVGSEYGCGMNPARHA-
		TPAYPARLLPRYR
DCX26	41.	SGRTTSEISGLWGWGDDRS GYGWGNTLRPNYIP-
		YRQATNRHRYT
DCX33	42.	RWNWTVLPATGGHYVVTRSTDYHAINNHRPS-
		IPHQHPTPI
DCX36	43.	SWSSWNWSSKTTRLGDRATREGCGPSQSDGCPY-
		NGRLTTVKPRT
DCX39	44.	SGSLNAWQPRSWVGGAFRSHANNNLNPK-
		PTMVTRHPT
DCX42	45.	RYSGLSPRDNGPACSQEATLEGCGAQRLM-
		STRRKGRNSRPGWTL
DCX45	46.	SVGNDKTSRPVSFYGRVSDLWNASLMPK-
		RTPSSKRHDDG
hPEPT1
PAX9	47.	RWPSVGYKGNGSDTIDVHSNDASTKRS-
		LIYNHRRPLFP
PAX14	48.	RTFENDGLGVGRSIQKKSDRWYASHN-
		IRSHFASMSPAGK
PAX15	49.	SYCRVKGGGEGGHTDSNLARSGCGKVAR-
		TSRLQHINPRATPPSR
PAX16	50.	SWTRWGKHTHGGFVNKSPPGKNATSPYTDA
		QLPSDQGPP
PAX17	51.	SQVDSFRNSFRWYEPSRALCHGCGKRDTS-
		TTRIHNSPSDSYPTR
PAX18	52.	SFLRFQSPRFEDYSRTISRLRN-
		ATNPSNVSDAHNNRALA
PAX35	53.	RSITDGGINEVDLSSVSNVLENANS-
		HRAYRKHRPTLKRP
PAX38	54.	SSKVSSPRDPTVPRKGGNVDYGCG-
		HRSSARMPTSALSSITKCYT
PAX40	55.	RASTQGGRGVAPEFGASVLGRGCGS-
		ATYYTNSTSCKDAMGHNYS
PAX43	56.	RWCEKHKFTAARCSAGAGFERDAS-
		RPPQPAHRDNTNRNA
PAX45	57.	SFQVYPDHGLERHALDGTGPLYAMP-
		GRWIRARPQNRDRQ
PAX46	58.	SRCTDNEQCPDTGTRSRSVSNARYFS-
		SRLLKTHAPHRP
P31	59.	SARDSGPAEDGSRAVRLNGVENANTRK-
		SSRSNPRGRRHP
P90	60.	SSADAEKCAGSLLWWGRQNNSGCGSP-
		JKKHLKHRNRSQTSSSSH
5PAX3	61.	RPKNVADAYSSQDGAAAEETSHASN-
		MRKSPKHKPLRRP
5PAX5	62.	RGSTGTAGGERSGVLNLHTRDNA
		SGSGFKPWYPSNRGHK
SPAX7	63.	RWGWERSPSDYDSDMDLGARRYA-
		TRTHRAPPRVLKAPLP
5PAX-	64.	RGWKCEGSQMYGDKDIGRSRGCG-
12		SITKNNTNHAHPSHGAVAKI
HPT-1
HAX9	65.	SREEANWDGYKREMSHRSRFWDA-
		THLSRPRRPANSGDPN
HAX35	66.	EWYSWKRSSKSTGLGDTATREGC-
		GPSQSDGCPYNGRLTTVKPRK
HAX40	67.	REFAERRLWGCDDLSWRLDAEG-
		CGPTPSNRAVKHRKPRPRSPAL
HAX42	68.	SDHALGTNLRSDNAKEPGDYNC-
		CGNGNSTGRKVFNRRRPSAIPT
HCA3	69.	RHISEYSFANSHLMGGESKRKGCGI-
		NGSFSPTCPRSPTPAFRRT
H40	70.	SRESGMWGSWWRGHRLNSTGGNA-
		NMNASLPPDPPVSTP
PAX2	71.	STPPSREAYSRPYSVDSDSDTNAKH-
		SSHNRRLRTRSRPN

These antibodies can be used in methods relating to the localization and activity of the GIT targeting agent sequences, e.g., for imaging these peptides after in vivo administration (e.g., to monitor treatment efficacy), measuring levels thereof in appropriate physiological samples, in diagnostic methods, etc. For instance, antibodies or antibody fragments specific to a domain of a GIT targeting agent, such as a dansyl group or some other epitope introduced into the peptide, can be used to 1) identify the presence of the peptide on a nanoparticle or other substrate; 2) quantify the amount of peptide on the nanoparticle; 3) measure the level of the peptide in appropriate physiological samples; 4) perform immunohistology on tissue samples; 5) image the peptide after in vivo administration; 6) purify the peptide from a mixture using an immunoaffinity column, 7) bind or fix the peptide to the surface of nanoparticle or 8) when a tag is also added to either an active-agent containing particle or the active agent itself, track the fate of both the particle/active agent and the GIT targeting agent so as to determine if and/or where they become separated. Use 7 above envisions attaching the antibody (or fragment of the antibody) to the surface of drug-loaded nanoparticles or other substrates and then incubating this conjugate with the peptide. This procedure results in binding of the peptide in a certain fixed orientation, resulting in a particle that contains the peptide bound to the antibody in such a way that the peptide is fully active. Additionally, antibodies or antibody fragments specific to a domain of a GIT targeting agent 9) can be used in confocal microscopy imaging techniques or other imaging techniques in order to demonstrate or confirm or identify the location or localization of the peptide on the surface of a nano- or microparticle, 10) can be used in confocal microscopy imaging techniques or other imaging techniques in order to demonstrate or confirm or identify the location or localization of the peptide on the surface of a nanoparticle or microparticle which has also been loaded with a fluorescent agent, 11) in the case of nanoparticles or microparticles coated with the peptide which have been sliced into two halves by a microtone or other suitable techniques, the antibody can be used in suitable quantitative techniques such as confocal microscopy imaging techniques or other quantitative imaging techniques in order to identify or quantitate the relative distribution of the peptide between the surface of the nanoparticle or microparticle and the sub-surface interior matrix of the nanoparticles or microparticles, 12) can be used in confocal microscopy imaging techniques or other imaging techniques in order to demonstrate or confirm or identify the location of a peptide on the surface of a nanoparticle or microparticle which has been loaded with a fluorescent agent such as TRME or fluorascene, 13) can be used to identify which epitope or domain of the peptide is responsible for identification by the antibody; peptide derivatives such as cyclic forms or derivatives containing intra-chain disulphide bonds or other intra-chain bonds can also be used in mapping studies in order to identify which domain or epitope of the peptide is responsible for recognition by the antibody; 14) in the case of peptide derivatives in which the epitope or domain responsible for binding to a target receptor is flanked by di-sulphide bond or other intra-chain bonds and in which this domain is also responsible for binding to the antibody, the antibody can be used to determine if that epitope or domain is exposed or available for binding to the antibody when the peptide or derivative is coated onto the surface of a nanoparticle, microparticle or other substance, 15) can be used where the epitope or domain on the peptide which binds to the target receptors in the human gastro-intestinal tract or the target receptors on model epithelial cells such as Caco-2 cells or polarised Caco-2 cells and where this epitope or domain on the peptide is also responsible for binding by the antibody, the antibody can be used in competition studies to compete for the binding of the peptide to its target receptor sites and 16) where the epitope or domain on the peptide which binds to the target receptors in the human gastro-intestinal or the target receptors on model epithelial cells such as Caco-2 cells or polarised Caco-2 cells and where this epitope or domain on the peptide is also responsible for binding by the antibody, the antibody can be used in competition studies in which nanoparticles or microparticles are coated with the peptide and are used in cell binding studies and/or in receptor binding studies.

Polyclonal antibodies against the GIT targeting agents PAX2 15 mer, HAX42-2 20mer and P31 D-form 16mer were raised to allow for, among other uses as discussed above, following the destiny of particles coated with peptides in in vivo models. These three GIT targeting agents were selected for their ability to bind in vitro to Caco-2 P100 fraction and, when coated on the surface of insulin loaded nanoparticles, to enhance insulin delivery in in vivo studies (rat model/intra-duodenal). The primary sequences for these three GIT targeting agents are given in Table 1.

TABLE 1
		N o of AMINO
Name	Sequence	ACIDS
ZElan033	K(dns)-TNAKHSSHNRRTRTR	PAX2 15 mer
	(SEQ ID NO: 1)
ZElan088	K(dns)-SDNAKEPGDYNCCGNGNSTG	HAX-42-2
	(SEQ ID NO: 2)	20 mer
ZElan053	K(dns)-TrKSSrSNPrGrrHPG	P31 D form
	(SEQ ID NO: 3)	16 mer

The peptides were synthesised (Genosys) and conjugated to KLH protein in preparation to immunise rabbits. KLH protein was conjugated at both N- and C-terminals in order to maximise the probability of obtaining specific antibodies.

The immunization protocol provided that two rabbits were immunized for each peptide; Rabbits 122 and 123 were immunized with PAX215 mer, Rabbits 120 and 121 were immunized with HAX42-2 20 mer and Rabbits 141 and 142 were immunized with P31 D-form 16mer. The initial immunisation was given in Complete Freund's adjuvant and the remaining boosts in Incomplete Freunds. A pre-immune sample was taken from each animal before immunization. The rabbits were injected at day 0, day 14 and 28, bled a week later at day 35 (1 st bleed), boosted a week later at day 42 and bled a week later at day 49; this sequence of injections and bleeds was performed every two weeks.

The bleed samples were tested by ELISA using the following procedures: 96 well plates were coated with peptide at 50 μg/ml in 0.05M carbonate/bicarbonate buffer, pH9.6, overnight. The plates were washed twice with PBS+0.05% Tween20 and the plates were blocked with 2% dried skimmed milk (99% fat free) in PBS for one hour at room temperature. The plates were then washed three times with PBS+0.05% Tween20 and anti-sera diluted in 2% dried milk-PBS was added followed by incubation for one hour at room temperature. The plates were then washed three times with PBS+0.05% Tween20 and secondary antibody goat anti-rabbit IgG-HRP (Sigma A0545, dilution 1:20000) in 2% dried milk-PBS was added followed by incubation for one hour at room temperature. The plates were washed three times with PBS+0.05% Tween20, TMB substrate was added, incubated and the absorbance was read at 650 nm.

The fourth bleed samples were tested by ELISA on both the peptides used for immunisation (but not conjugated to KLH) and on different (dansylated) peptide batches. Pre-immune serum was included in the assay as negative control and background binding to plastic was also tested. As shown in FIG. 1 , the antisera of the immunised rabbits gave an antibody response compared to pre-immune sera of the same animals. The immuno response of the two rabbits immunised in each protocol was comparable except that Rabbit 120 showed a lower antibody titer with respect to Rabbit 121. Crossreactivity of each rabbit antiserum on different peptides was also analysed by ELISA as shown in FIG. 2 and no significant cross-reactivity was detected.

The fifth bleed samples were tested by ELISA as described above and examples of the profiles obtained are shown in FIGS. 3 , 4 and 5 . A higher titer of antibody was detected for each rabbit after this longer immunisation period compared to the fourth bleed results.

FIG. 3 shows the immuno-reaction of anti-HAX42 antisera on synthetic peptides (sequences reported in the Figure). Panel A shows the ELISA results for rabbit # 120 antisera: good immuno-response is obtained on unconjugated peptide used as antigen but no response was obtained for the same peptide conjugated to a dansyl group (Zelan088). No immuno-response is observed for the other peptides analysed. Panel B shows the ELISA results for rabbit # 121 antisera: in this case there also was good immuno-response for the unconjugated peptide used as antigen but no response for Zelan088 dansyl-peptide. Rabbit # 121 antisera is positive (although less strongly) against Zelan021 (HAX42) and Zelan071 (HAX42 29 mer derivative). Panel C shows the response of anti-dansyl IgG on the peptides used in the assay.

FIG. 4 shows the immuno-reactivity of anti-PAX2 antisera on synthetic peptides. Rabbit # 122 (panel A) and # 123 (panel B) have a different immuno-response. Both antisera react in the same way to the unconjugated peptide (=Zelan033) used for immunisation. Rabbit # 123 antisera has also very strong reactivity against Zelan103A peptide whereas rabbit # 122 does not bind to the same peptide. Rabbit # 123 antisera has also imuno-response against both Zelan104 and Zelan108. Panel C shows the response of anti-dansyl IgG on the peptides used in the assay.

FIG. 5 shows the immuno-reactivity of anti-P31 D-form antisera on synthetic peptides. Both rabbit # 141 and # 142 react equally well on P31 D-form unconjugated peptide (=Zelan053). No reactivity is present against all the other peptides tested.

Table 2 provides a summary of the fifth bleed results.

	TABLE 2
	Rabbit
	Number	Peptides
		Zelan021	Zelan071	Zelan088	Unconjug.
					antigen
					(= Zelan088)
	Rabbit	−	−	−	+
	120
(HAX-	Rabbit	+	+/−	−/+	++
42)	121
		Zelan018	Zelan104	Unconjug.	Zelan103A
				antigen
				(= Zelan033)
	Rabbit	−/+	−/+	+	−
	122
(PAX2)	Rabbit	+	+	+	++
	123
		Zelan024	Unconjug.	Zelan054	Zelan145
			antigen
			(= Zelan053)
(P31	Rabbit	−	+	−	−
d-form)	141
	Rabbit	−	+	−	−
	142

The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

84 1 15 PRT Artificial Sequence Random peptide 1Thr Asn Ala Lys His Ser Ser His Asn Arg Arg Leu Arg Thr Arg1 5 10 15 2 20 PRT Artificial Sequence Random peptide 2Ser Asp Asn Ala Lys Glu Pro Gly Asp Tyr Asn Cys Cys Gly Asn Gly1 5 10 15Asn Ser Thr Gly 20 3 16 PRT Artificial Sequence Random peptide 3Thr Arg Lys Ser Ser Arg Ser Asn Pro Arg Gly Arg Arg His Pro Gly1 5 10 15 4 36 PRT Artificial Sequence Random peptide 4Ser Asp His Ala Leu Gly Thr Asn Leu Arg Ser Asp Asn Ala Lys Glu1 5 10 15Pro Gly Asp Tyr Asn Cys Cys Gly Asn Gly Asn Ser Thr Gly Arg Lys 20 25 30Val Phe Asn Arg 35 5 29 PRT Artificial sequence Random peptide 5Asn Leu Arg Ser Asp Asn Ala Lys Glu Pro Gly Asp Tyr Asn Cys Cys1 5 10 15Gly Asn Gly Asn Ser Thr Gly Arg Lys Val Phe Asn Arg 20 25 6 20 PRT Artificial Sequence Random sequence 6Ser Asp Asn Ala Lys Glu Pro Gly Asp Tyr Asn Cys Cys Gly Asn Gly1 5 10 15Asn Ser Thr Gly 20 7 40 PRT Artificial Sequence Random peptide 7Ser Thr Pro Pro Ser Arg Glu Ala Tyr Ser Arg Pro Tyr Ser Val Asp1 5 10 15Ser Asp Ser Asp Thr Asn Ala Lys His Ser Ser His Asn Arg Arg Leu 20 25 30Arg Thr Arg Ser Arg Pro Asn Gly 35 40 8 15 PRT Artificial Sequence Cyclic (internal) random peptide 8Thr Asn Ala Lys His Ser Ser Cys Asn Arg Arg Leu Arg Cys Arg1 5 10 15 9 15 PRT Artificial Sequence Cyclic (internal) random peptide 9Thr Asn Ala Lys His Ser Ser Cys Asn Arg Arg Cys Arg Thr Arg1 5 10 15 10 41 PRT Artificial Sequence Random peptide 10Ser Ala Arg Asp Ser Gly Pro Ala Glu Asp Gly Ser Arg Ala Val Arg1 5 10 15Leu Asn Gly Val Glu Asn Ala Asn Thr Arg Lys Ser Ser Arg Ser Asn 20 25 30Pro Arg Gly Arg Arg His Pro Gly Gly 35 40 11 16 PRT Artificial Sequence Random peptide 11Thr Arg Lys Ser Ser Arg Ser Asn Pro Arg Gly Arg Arg His Pro Gly1 5 10 15 12 16 PRT Artificial Sequence Random peptide, D form, retroinversion 12Gly Pro His Arg Arg Gly Arg Pro Asn Ser Arg Ser Ser Lys Arg Thr1 5 10 15 13 685 PRT Artificial D2H receptor 13Met Ala Glu Asp Lys Ser Lys Arg Asp Ser Ile Glu Met Ser Met Lys1 5 10 15Gly Cys Gln Thr Asn Asn Gly Phe Val His Asn Glu Asp Ile Leu Glu 20 25 30Gln Thr Pro Asp Pro Gly Ser Ser Thr Asp Asn Leu Lys His Ser Thr 35 40 45Arg Gly Ile Leu Gly Ser Gln Glu Pro Asp Phe Lys Gly Val Gln Pro 50 55 60Tyr Ala Gly Met Pro Lys Glu Val Leu Phe Gln Phe Ser Gly Gln Ala65 70 75 80Arg Tyr Arg Ile Pro Arg Glu Ile Leu Phe Trp Leu Thr Val Ala Ser 85 90 95Val Leu Val Leu Ile Ala Ala Thr Ile Ala Ile Ile Ala Leu Ser Pro 100 105 110Lys Cys Leu Asp Trp Trp Gln Glu Gly Pro Met Tyr Gln Ile Tyr Pro 115 120 125Arg Ser Phe Lys Asp Ser Asn Lys Asp Gly Asn Gly Asp Leu Lys Gly 130 135 140Ile Gln Asp Lys Leu Asp Tyr Ile Thr Ala Leu Asn Ile Lys Thr Val145 150 155 160Trp Ile Thr Ser Phe Tyr Lys Ser Ser Leu Lys Asp Phe Arg Tyr Gly 165 170 175Val Glu Asp Phe Arg Glu Val Asp Pro Ile Phe Gly Thr Met Glu Asp 180 185 190Phe Glu Asn Leu Val Ala Ala Ile His Asp Lys Gly Leu Lys Leu Ile 195 200 205Ile Asp Phe Ile Pro Asn His Thr Ser Asp Lys His Ile Trp Phe Gln 210 215 220Leu Ser Arg Thr Arg Thr Gly Lys Tyr Thr Asp Tyr Tyr Ile Trp His225 230 235 240Asp Cys Thr His Glu Asn Gly Lys Thr Ile Pro Pro Asn Asn Trp Leu 245 250 255Ser Val Tyr Gly Asn Ser Ser Trp His Phe Asp Glu Val Arg Asn Gln 260 265 270Cys Tyr Phe His Gln Phe Met Lys Glu Gln Pro Asp Leu Asn Phe Arg 275 280 285Asn Pro Asp Val Gln Glu Glu Ile Lys Glu Ile Leu Arg Phe Trp Leu 290 295 300Thr Lys Gly Val Asp Gly Phe Ser Leu Asp Ala Val Lys Phe Leu Leu305 310 315 320Glu Ala Lys His Leu Arg Asp Glu Ile Gln Val Asn Lys Thr Gln Ile 325 330 335Pro Asp Thr Val Thr Gln Tyr Ser Glu Leu Tyr His Asp Phe Thr Thr 340 345 350Thr Gln Val Gly Met His Asp Ile Val Arg Ser Phe Arg Gln Thr Met 355 360 365Asp Gln Tyr Ser Thr Glu Pro Gly Arg Tyr Arg Phe Met Gly Thr Glu 370 375 380Ala Tyr Ala Glu Ser Ile Asp Arg Thr Val Met Tyr Tyr Gly Leu Pro385 390 395 400Phe Ile Gln Glu Ala Asp Phe Pro Phe Asn Asn Tyr Leu Ser Met Leu 405 410 415Asp Thr Val Ser Gly Asn Ser Val Tyr Glu Val Ile Thr Ser Trp Met 420 425 430Glu Asn Met Pro Glu Gly Lys Trp Pro Asn Trp Met Ile Gly Gly Pro 435 440 445Asp Ser Ser Arg Leu Thr Ser Arg Leu Gly Asn Gln Tyr Val Asn Val 450 455 460Met Asn Met Leu Leu Phe Thr Leu Pro Gly Thr Pro Ile Thr Tyr Tyr465 470 475 480Gly Glu Glu Ile Gly Met Gly Asn Ile Val Ala Ala Asn Leu Asn Glu 485 490 495Ser Tyr Asp Ile Asn Thr Leu Arg Ser Lys Ser Pro Met Gln Trp Asp 500 505 510Asn Ser Ser Asn Ala Gly Phe Ser Glu Ala Ser Asn Thr Trp Leu Pro 515 520 525Thr Asn Ser Asp Tyr His Thr Val Asn Val Asp Val Gln Lys Thr Gln 530 535 540Pro Arg Ser Ala Leu Lys Leu Tyr Gln Asp Leu Ser Leu Leu His Ala545 550 555 560Asn Glu Leu Leu Leu Asn Arg Gly Trp Phe Cys His Leu Arg Asn Asp 565 570 575Ser His Tyr Val Val Tyr Thr Arg Glu Leu Asp Gly Ile Asp Arg Ile 580 585 590Phe Ile Val Val Leu Asn Phe Gly Glu Ser Thr Leu Leu Asn Leu His 595 600 605Asn Met Ile Ser Gly Leu Pro Ala Lys Ile Arg Ile Arg Leu Ser Thr 610 615 620Asn Ser Ala Asp Lys Gly Ser Lys Val Asp Thr Ser Gly Ile Phe Leu625 630 635 640Asp Lys Gly Glu Gly Leu Ile Phe Glu His Asn Thr Lys Asn Leu Leu 645 650 655His Arg Gln Thr Ala Phe Arg Asp Arg Cys Phe Val Ser Asn Arg Ala 660 665 670Cys Tyr Ser Ser Val Leu Asn Ile Leu Tyr Thr Ser Cys 675 680 685 14 1827 PRT Artificial hSI receptor 14Met Ala Arg Lys Lys Phe Ser Gly Leu Glu Ile Ser Leu Ile Val Leu1 5 10 15Phe Val Ile Val Thr Ile Ile Ala Ile Ala Leu Ile Val Val Leu Ala 20 25 30Thr Lys Thr Pro Ala Val Asp Glu Ile Ser Asp Ser Thr Ser Thr Pro 35 40 45Ala Thr Thr Arg Val Thr Thr Asn Pro Ser Asp Ser Gly Lys Cys Pro 50 55 60Asn Val Leu Asn Asp Pro Val Asn Val Arg Ile Asn Cys Ile Pro Glu65 70 75 80Gln Phe Pro Thr Glu Gly Ile Cys Ala Gln Arg Gly Cys Cys Trp Arg 85 90 95Pro Trp Asn Asp Ser Leu Ile Pro Trp Cys Phe Phe Val Asp Asn His 100 105 110Gly Tyr Asn Val Gln Asp Met Thr Thr Thr Ser Ile Gly Val Glu Ala 115 120 125Lys Leu Asn Arg Ile Pro Ser Pro Thr Leu Phe Gly Asn Asp Ile Asn 130 135 140Ser Val Leu Phe Thr Thr Gln Asn Gln Thr Pro Asn Arg Phe Arg Phe145 150 155 160Lys Ile Thr Asp Pro Asn Asn Arg Arg Tyr Glu Val Pro His Gln Tyr 165 170 175Val Lys Glu Phe Thr Gly Pro Thr Val Ser Asp Thr Leu Tyr Asp Val 180 185 190Lys Val Ala Gln Asn Pro Phe Ser Ile Gln Val Ile Arg Lys Ser Asn 195 200 205Gly Lys Thr Leu Phe Asp Thr Ser Ile Gly Pro Leu Val Tyr Ser Asp 210 215 220Gln Tyr Leu Gln Ile Ser Ala Arg Leu Pro Ser Asp Tyr Ile Tyr Gly225 230 235 240Ile Gly Glu Gln Val His Lys Arg Phe Arg His Asp Leu Ser Trp Lys 245 250 255Thr Trp Pro Ile Phe Thr Arg Asp Gln Leu Pro Gly Asp Asn Asn Asn 260 265 270Asn Leu Tyr Gly His Gln Thr Phe Phe Met Cys Ile Glu Asp Thr Ser 275 280 285Gly Lys Ser Phe Gly Val Phe Leu Met Asn Ser Asn Ala Met Glu Ile 290 295 300Phe Ile Gln Pro Thr Pro Ile Val Thr Tyr Arg Val Thr Gly Gly Ile305 310 315 320Leu Asp Phe Tyr Ile Leu Leu Gly Asp Thr Pro Glu Gln Val Val Gln 325 330 335Gln Tyr Gln Gln Leu Val Gly Leu Pro Ala Met Pro Ala Tyr Trp Asn 340 345 350Leu Gly Phe Gln Leu Ser Arg Trp Asn Tyr Lys Ser Leu Asp Val Val 355 360 365Lys Glu Val Val Arg Arg Asn Arg Glu Ala Gly Ile Pro Phe Asp Thr 370 375 380Gln Val Thr Asp Ile Asp Tyr Met Glu Asp Lys Lys Asp Phe Thr Tyr385 390 395 400Asp Gln Val Ala Phe Asn Gly Leu Pro Gln Phe Val Gln Asp Leu His 405 410 415Asp His Gly Gln Lys Tyr Val Ile Ile Leu Asp Pro Ala Ile Ser Ile 420 425 430Gly Arg Arg Ala Asn Gly Thr Thr Tyr Ala Thr Tyr Glu Arg Gly Asn 435 440 445Thr Gln His Val Trp Ile Asn Glu Ser Asp Gly Ser Thr Pro Ile Ile 450 455 460Gly Glu Val Trp Pro Gly Leu Thr Val Tyr Pro Asp Phe Thr Asn Pro465 470 475 480Asn Cys Ile Asp Trp Trp Ala Asn Glu Cys Ser Ile Phe His Gln Glu 485 490 495Val Gln Tyr Asp Gly Leu Trp Ile Asp Met Asn Glu Val Ser Ser Phe 500 505 510Ile Gln Gly Ser Thr Lys Gly Cys Asn Val Asn Lys Leu Asn Tyr Pro 515 520 525Pro Phe Thr Pro Asp Ile Leu Asp Lys Leu Met Tyr Ser Lys Thr Ile 530 535 540Cys Met Asp Ala Val Gln Asn Trp Gly Lys Gln Tyr Asp Val His Ser545 550 555 560Leu Tyr Gly Tyr Ser Met Ala Ile Ala Thr Glu Gln Ala Val Gln Lys 565 570 575Val Phe Pro Asn Lys Arg Ser Phe Ile Leu Thr Arg Ser Thr Phe Ala 580 585 590Gly Ser Gly Arg His Ala Ala His Trp Leu Gly Asp Asn Thr Ala Ser 595 600 605Trp Glu Gln Met Glu Trp Ser Ile Thr Gly Met Leu Glu Phe Ser Leu 610 615 620Phe Gly Ile Pro Leu Val Gly Ala Asp Ile Cys Gly Phe Val Ala Glu625 630 635 640Thr Thr Glu Glu Leu Cys Arg Arg Trp Met Gln Leu Gly Ala Phe Tyr 645 650 655Pro Phe Ser Arg Asn His Asn Ser Asp Gly Tyr Glu His Gln Asp Pro 660 665 670Ala Phe Phe Gly Gln Asn Ser Leu Leu Val Lys Ser Ser Arg Gln Tyr 675 680 685Leu Thr Ile Arg Tyr Thr Leu Leu Pro Phe Leu Tyr Thr Leu Phe Tyr 690 695 700Lys Ala His Val Phe Gly Glu Thr Val Ala Arg Pro Val Leu His Glu705 710 715 720Phe Tyr Glu Asp Thr Asn Ser Trp Ile Glu Asp Thr Glu Phe Leu Trp 725 730 735Gly Pro Ala Leu Leu Ile Thr Pro Val Leu Lys Gln Gly Ala Asp Thr 740 745 750Val Ser Ala Tyr Ile Pro Asp Ala Ile Trp Tyr Asp Tyr Glu Ser Gly 755 760 765Ala Lys Arg Pro Trp Arg Lys Gln Arg Val Asp Met Tyr Leu Pro Ala 770 775 780Asp Lys Ile Gly Leu His Leu Arg Gly Gly Tyr Ile Ile Pro Ile Gln785 790 795 800Glu Pro Asp Val Thr Thr Thr Ala Ser Arg Lys Asn Pro Leu Gly Leu 805 810 815Ile Val Ala Leu Gly Glu Asn Asn Thr Ala Lys Gly Asp Phe Phe Trp 820 825 830Asp Asp Gly Glu Thr Lys Asp Thr Ile Gln Asn Gly Asn Tyr Ile Leu 835 840 845Tyr Thr Phe Ser Val Ser Asn Asn Thr Leu Asp Ile Val Cys Thr His 850 855 860Ser Ser Tyr Gln Glu Gly Thr Thr Leu Ala Phe Gln Thr Val Lys Ile865 870 875 880Leu Gly Leu Thr Asp Ser Val Thr Glu Val Arg Val Ala Glu Asn Asn 885 890 895Gln Pro Met Asn Ala His Ser Asn Phe Thr Tyr Asp Ala Ser Asn Gln 900 905 910Val Leu Leu Ile Ala Asp Leu Lys Leu Asn Leu Gly Arg Asn Phe Ser 915 920 925Val Gln Trp Asn Gln Ile Phe Ser Glu Asn Glu Arg Phe Asn Cys Tyr 930 935 940Pro Asp Ala Asp Leu Ala Thr Glu Gln Lys Cys Thr Gln Arg Gly Cys945 950 955 960Val Trp Arg Thr Gly Ser Ser Leu Ser Lys Ala Pro Glu Cys Tyr Phe 965 970 975Pro Arg Gln Asp Asn Ser Tyr Ser Val Asn Ser Ala Arg Tyr Ser Ser 980 985 990Met Gly Ile Thr Ala Asp Leu Gln Leu Asn Thr Ala Asn Ala Arg Ile 995 1000 1005Lys Leu Pro Ser Asp Pro Ile Ser Thr Leu Arg Val Glu Val Lys 1010 1015 1020Tyr His Lys Asn Asp Met Leu Gln Phe Lys Ile Tyr Asp Pro Gln 1025 1030 1035Lys Lys Arg Tyr Glu Val Pro Val Pro Leu Asn Ile Pro Thr Thr 1040 1045 1050Pro Ile Ser Thr Tyr Glu Asp Arg Leu Tyr Asp Val Glu Ile Lys 1055 1060 1065Glu Asn Pro Phe Gly Ile Gln Ile Arg Arg Arg Ser Ser Gly Arg 1070 1075 1080Val Ile Trp Asp Ser Trp Leu Pro Gly Phe Ala Phe Asn Asp Gln 1085 1090 1095Phe Ile Gln Ile Ser Thr Arg Leu Pro Ser Glu Tyr Ile Tyr Gly 1100 1105 1110Phe Gly Glu Val Glu His Thr Ala Phe Lys Arg Asp Leu Asn Trp 1115 1120 1125Asn Thr Trp Gly Met Phe Thr Arg Asp Gln Pro Pro Gly Tyr Lys 1130 1135 1140Leu Asn Ser Tyr Gly Phe His Pro Tyr Tyr Met Ala Leu Glu Glu 1145 1150 1155Glu Gly Asn Ala His Gly Val Phe Leu Leu Asn Ser Asn Ala Met 1160 1165 1170Asp Val Thr Phe Gln Pro Thr Pro Ala Leu Thr Tyr Arg Thr Val 1175 1180 1185Gly Gly Ile Leu Asp Phe Tyr Met Phe Leu Gly Pro Thr Pro Gln 1190 1195 1200Val Ala Thr Lys Gln Tyr His Glu Val Ile Gly His Pro Val Met 1205 1210 1215Pro Ala Tyr Trp Ala Leu Gly Phe Gln Leu Cys Arg Tyr Gly Tyr 1220 1225 1230Ala Asn Thr Ser Glu Val Arg Glu Leu Tyr Asp Ala Met Val Ala 1235 1240 1245Ala Asn Ile Pro Tyr Asp Val Gln Tyr Thr Asp Ile Asp Tyr Met 1250 1255 1260Glu Arg Gln Leu Asp Phe Thr Ile Gly Glu Ala Phe Gln Asp Leu 1265 1270 1275Pro Gln Phe Val Asp Lys Ile Arg Gly Glu Gly Met Arg Tyr Ile 1280 1285 1290Ile Ile Leu Asp Pro Ala Ile Ser Gly Asn Glu Thr Lys Thr Tyr 1295 1300 1305Pro Ala Phe Glu Arg Gly Gln Gln Asn Asp Val Phe Val Lys Trp 1310 1315 1320Pro Asn Thr Asn Asp Ile Cys Trp Ala Lys Val Trp Pro Asp Leu 1325 1330 1335Pro Asn Ile Thr Ile Asp Lys Thr Leu Thr Glu Asp Glu Ala Val 1340 1345 1350Asn Ala Ser Arg Ala His Val Ala Phe Pro Asp Phe Phe Arg Thr 1355 1360 1365Ser Thr Ala Glu Trp Trp Ala Arg Glu Ile Val Asp Phe Tyr Asn 1370 1375 1380Glu Lys Met Lys Phe Asp Gly Leu Trp Ile Asp Met Asn Glu Pro 1385 1390 1395Ser Ser Phe Val Asn Gly Thr Thr Thr Asn Gln Cys Arg Asn Asp 1400 1405 1410Glu Leu Asn Tyr Pro Pro Tyr Phe Pro Glu Leu Thr Lys Arg Thr 1415 1420 1425Asp Gly Leu His Phe Arg Thr Ile Cys Met Glu Ala Glu Gln Ile 1430 1435 1440Leu Ser Asp Gly Thr Ser Val Leu His Tyr Asp Val His Asn Leu 1445 1450 1455Tyr Gly Trp Ser Gln Met Lys Pro Thr His Asp Ala Leu Gln Lys 1460 1465 1470Thr Thr Gly Lys Arg Gly Ile Val Ile Ser Arg Ser Thr Tyr Pro 1475 1480 1485Thr Ser Gly Arg Trp Gly Gly His Trp Leu Gly Asp Asn Tyr Ala 1490 1495 1500Arg Trp Asp Asn Met Asp Lys Ser Ile Ile Gly Met Met Glu Phe 1505 1510 1515Ser Leu Phe Gly Ile Ser Tyr Thr Gly Ala Asp Ile Cys Gly Phe 1520 1525 1530Phe Asn Asn Ser Glu Tyr His Leu Cys Thr Arg Trp Met Gln Leu 1535 1540 1545Gly Ala Phe Tyr Pro Tyr Ser Arg Asn His Asn Ile Ala Asn Thr 1550 1555 1560Arg Arg Gln Asp Pro Ala Ser Trp Asn Glu Thr Phe Ala Glu Met 1565 1570 1575Ser Arg Asn Ile Leu Asn Ile Arg Tyr Thr Leu Leu Pro Tyr Phe 1580 1585 1590Tyr Thr Gln Met His Glu Ile His Ala Asn Gly Gly Thr Val Ile 1595 1600 1605Arg Pro Leu Leu His Glu Phe Phe Asp Glu Lys Pro Thr Trp Asp 1610 1615 1620Ile Phe Lys Gln Phe Leu Trp Gly Pro Ala Phe Met Val Thr Pro 1625 1630 1635Val Leu Glu Pro Tyr Val Gln Thr Val Asn Ala Tyr Val Pro Asn 1640 1645 1650Ala Arg Trp Phe Asp Tyr His Thr Gly Lys Asp Ile Gly Val Arg 1655 1660 1665Gly Gln Phe Gln Thr Phe Asn Ala Ser Tyr Asp Thr Ile Asn Leu 1670 1675 1680His Val Arg Gly Gly His Ile Leu Pro Cys Gln Glu Pro Ala Gln 1685 1690 1695Asn Thr Phe Tyr Ser Arg Gln Lys His Met Lys Leu Ile Val Ala 1700 1705 1710Ala Asp Asp Asn Gln Met Ala Gln Gly Ser Leu Phe Trp Asp Asp 1715 1720 1725Gly Glu Ser Ile Asp Thr Tyr Glu Arg Asp Leu Tyr Leu Ser Val 1730 1735 1740Gln Phe Asn Leu Asn Gln Thr Thr Leu Thr Ser Thr Ile Leu Lys 1745 1750 1755Arg Gly Tyr Ile Asn Lys Ser Glu Thr Arg Leu Gly Ser Leu His 1760 1765 1770Val Trp Gly Lys Gly Thr Thr Pro Val Asn Ala Val Thr Leu Thr 1775 1780 1785Tyr Asn Gly Asn Lys Asn Ser Leu Pro Phe Asn Glu Asp Thr Thr 1790 1795 1800Asn Met Ile Leu Arg Ile Asp Leu Thr Thr His Asn Val Thr Leu 1805 1810 1815Glu Glu Pro Ile Glu Ile Asn Trp Ser 1820 1825 15 832 PRT Artificial HPT1 receptor 15Met Ile Leu Gln Ala His Leu His Ser Leu Cys Leu Leu Met Leu Tyr1 5 10 15Leu Ala Thr Gly Tyr Gly Gln Glu Gly Lys Phe Ser Gly Pro Leu Lys 20 25 30Pro Met Thr Phe Ser Ile Tyr Glu Gly Gln Glu Pro Ser Gln Ile Ile 35 40 45Phe Gln Phe Lys Ala Asn Pro Pro Ala Val Thr Phe Glu Leu Thr Gly 50 55 60Glu Thr Asp Asn Ile Phe Val Ile Glu Arg Glu Gly Leu Leu Tyr Tyr65 70 75 80Asn Arg Ala Leu Asp Arg Glu Thr Arg Ser Thr His Asn Leu Gln Val 85 90 95Ala Ala Leu Asp Ala Asn Gly Ile Ile Val Glu Gly Pro Val Pro Ile 100 105 110Thr Ile Glu Val Lys Asp Ile Asn Asp Asn Arg Pro Thr Phe Leu Gln 115 120 125Ser Lys Tyr Glu Gly Ser Val Arg Gln Asn Ser Arg Pro Gly Lys Pro 130 135 140Phe Leu Tyr Val Asn Ala Thr Asp Leu Asp Asp Pro Ala Thr Pro Asn145 150 155 160Gly Gln Leu Tyr Tyr Gln Ile Val Ile Gln Leu Pro Met Ile Asn Asn 165 170 175Val Met Tyr Phe Gln Ile Asn Asn Lys Thr Gly Ala Ile Ser Leu Thr 180 185 190Arg Glu Gly Ser Gln Glu Leu Asn Pro Ala Lys Asn Pro Ser Tyr Asn 195 200 205Leu Val Ile Ser Val Lys Asp Met Gly Gly Gln Ser Glu Asn Ser Phe 210 215 220Ser Asp Thr Thr Ser Val Asp Ile Ile Val Thr Glu Asn Ile Trp Lys225 230 235 240Ala Pro Lys Pro Val Glu Met Val Glu Asn Ser Thr Asp Pro His Pro 245 250 255Ile Lys Ile Thr Gln Val Arg Trp Asn Asp Pro Gly Ala Gln Tyr Ser 260 265 270Leu Val Asp Lys Glu Lys Leu Pro Arg Phe Pro Phe Ser Ile Asp Gln 275 280 285Glu Gly Asp Ile Tyr Val Thr Gln Pro Leu Asp Arg Glu Glu Lys Asp 290 295 300Ala Tyr Val Phe Tyr Ala Val Ala Lys Asp Glu Tyr Gly Lys Pro Leu305 310 315 320Ser Tyr Pro Leu Glu Ile His Val Lys Val Lys Asp Ile Asn Asp Asn 325 330 335Pro Pro Thr Cys Pro Ser Pro Val Thr Val Phe Glu Val Gln Glu Asn 340 345 350Glu Arg Leu Gly Asn Ser Ile Gly Thr Leu Thr Ala His Asp Arg Asp 355 360 365Glu Glu Asn Thr Ala Asn Ser Phe Leu Asn Tyr Arg Ile Val Glu Gln 370 375 380Thr Pro Lys Leu Pro Met Asp Gly Leu Phe Leu Ile Gln Thr Tyr Ala385 390 395 400Gly Met Leu Gln Leu Ala Lys Gln Ser Leu Lys Lys Gln Asp Thr Pro 405 410 415Gln Tyr Asn Leu Thr Ile Glu Val Ser Asp Lys Asp Phe Lys Thr Leu 420 425 430Cys Phe Val Gln Ile Asn Val Ile Asp Ile Asn Asp Gln Ile Pro Ile 435 440 445Phe Glu Lys Ser Asp Tyr Gly Asn Leu Thr Leu Ala Glu Asp Thr Asn 450 455 460Ile Gly Ser Thr Ile Leu Thr Ile Gln Ala Thr Asp Ala Asp Glu Pro465 470 475 480Phe Thr Gly Ser Ser Lys Ile Leu Tyr His Ile Ile Lys Gly Asp Ser 485 490 495Glu Gly Arg Leu Gly Val Asp Thr Asp Pro His Thr Asn Thr Gly Tyr 500 505 510Val Ile Ile Lys Lys Pro Leu Asp Phe Glu Thr Ala Ala Val Ser Asn 515 520 525Ile Val Phe Lys Ala Glu Asn Pro Glu Pro Leu Val Phe Gly Val Lys 530 535 540Tyr Asn Ala Ser Ser Phe Ala Lys Phe Thr Leu Ile Val Thr Asp Val545 550 555 560Asn Glu Ala Pro Gln Phe Ser Gln His Val Phe Gln Ala Lys Val Ser 565 570 575Glu Asp Val Ala Ile Gly Thr Lys Val Gly Asn Val Thr Ala Lys Asp 580 585 590Pro Glu Gly Leu Asp Ile Ser Tyr Ser Leu Arg Gly Asp Thr Arg Gly 595 600 605Trp Leu Lys Ile Asp His Val Thr Gly Glu Ile Phe Ser Val Ala Pro 610 615 620Leu Asp Arg Glu Ala Gly Ser Pro Tyr Arg Val Gln Val Val Ala Thr625 630 635 640Glu Val Gly Gly Ser Ser Leu Ser Ser Val Ser Glu Phe His Leu Ile 645 650 655Leu Met Asp Val Asn Asp Asn Pro Pro Arg Leu Ala Lys Asp Tyr Thr 660 665 670Gly Leu Phe Phe Cys His Pro Leu Ser Ala Pro Gly Ser Leu Ile Phe 675 680 685Glu Ala Thr Asp Asp Asp Gln His Leu Phe Arg Gly Pro His Phe Thr 690 695 700Phe Ser Leu Gly Ser Gly Ser Leu Gln Asn Asp Trp Glu Val Ser Lys705 710 715 720Ile Asn Gly Thr His Ala Arg Leu Ser Thr Arg His Thr Asp Phe Glu 725 730 735Glu Arg Ala Tyr Val Val Leu Ile Arg Ile Asn Asp Gly Gly Arg Pro 740 745 750Pro Leu Glu Gly Ile Val Ser Leu Pro Val Thr Phe Cys Ser Cys Val 755 760 765Glu Gly Ser Cys Phe Arg Pro Ala Gly His Gln Thr Gly Ile Pro Thr 770 775 780Val Gly Met Ala Val Gly Ile Leu Leu Thr Thr Leu Leu Val Ile Gly785 790 795 800Ile Ile Leu Ala Val Val Phe Ile Arg Ile Lys Lys Asp Lys Gly Lys 805 810 815Asp Asn Val Glu Ser Ala Gln Ala Ser Glu Val Lys Pro Leu Arg Ser 820 825 830 16 708 PRT Artificial hPEPT1 receptor 16Met Gly Met Ser Lys Ser His Ser Phe Phe Gly Tyr Pro Leu Ser Ile1 5 10 15Phe Phe Ile Val Val Asn Glu Phe Cys Glu Arg Phe Ser Tyr Tyr Gly 20 25 30Met Arg Ala Ile Leu Ile Leu Tyr Phe Thr Asn Phe Ile Ser Trp Asp 35 40 45Asp Asn Leu Ser Thr Ala Ile Tyr His Thr Phe Val Ala Leu Cys Tyr 50 55 60Leu Thr Pro Ile Leu Gly Ala Leu Ile Ala Asp Ser Trp Leu Gly Lys65 70 75 80Phe Lys Thr Ile Val Ser Leu Ser Ile Val Tyr Thr Ile Gly Gln Ala 85 90 95Val Thr Ser Val Ser Ser Ile Asn Asp Leu Thr Asp His Asn His Asp 100 105 110Gly Thr Pro Asp Ser Leu Pro Val His Val Val Leu Ser Leu Ile Gly 115 120 125Leu Ala Leu Ile Ala Leu Gly Thr Gly Gly Ile Lys Pro Cys Val Ser 130 135 140Ala Phe Gly Gly Asp Gln Phe Glu Glu Gly Gln Glu Lys Gln Arg Asn145 150 155 160Arg Phe Phe Ser Ile Phe Tyr Leu Ala Ile Asn Ala Gly Ser Leu Leu 165 170 175Ser Thr Ile Ile Thr Pro Met Leu Arg Val Gln Gln Cys Gly Ile His 180 185 190Ser Lys Gln Ala Cys Tyr Pro Leu Ala Phe Gly Val Pro Ala Ala Leu 195 200 205Met Ala Val Ala Leu Ile Val Phe Val Leu Gly Ser Gly Met Tyr Lys 210 215 220Lys Phe Lys Pro Gln Gly Asn Ile Met Gly Lys Val Ala Lys Cys Ile225 230 235 240Gly Phe Ala Ile Lys Asn Arg Phe Arg His Arg Ser Lys Ala Phe Pro 245 250 255Lys Arg Glu His Trp Leu Asp Trp Ala Lys Glu Lys Tyr Asp Glu Arg 260 265 270Leu Ile Ser Gln Ile Lys Met Val Thr Arg Val Met Phe Leu Tyr Ile 275 280 285Pro Leu Pro Met Phe Trp Ala Leu Phe Asp Gln Gln Gly Ser Arg Trp 290 295 300Thr Leu Gln Ala Thr Thr Met Ser Gly Lys Ile Gly Ala Leu Glu Ile305 310 315 320Gln Pro Asp Gln Met Gln Thr Val Asn Ala Ile Leu Ile Val Ile Met 325 330 335Val Pro Ile Phe Asp Ala Val Leu Tyr Pro Leu Ile Ala Lys Cys Gly 340 345 350Phe Asn Phe Thr Ser Leu Lys Lys Met Ala Val Gly Met Val Leu Ala 355 360 365Ser Met Ala Phe Val Val Ala Ala Ile Val Gln Val Glu Ile Asp Lys 370 375 380Thr Leu Pro Val Phe Pro Lys Gly Asn Glu Val Gln Ile Lys Val Leu385 390 395 400Asn Ile Gly Asn Asn Thr Met Asn Ile Ser Leu Pro Gly Glu Met Val 405 410 415Thr Leu Gly Pro Met Ser Gln Thr Asn Ala Phe Met Thr Phe Asp Val 420 425 430Asn Lys Leu Thr Arg Ile Asn Ile Ser Ser Pro Gly Ser Pro Val Thr 435 440 445Ala Val Thr Asp Asp Phe Lys Gln Gly Gln Arg His Thr Leu Leu Val 450 455 460Trp Ala Pro Asn His Tyr Gln Val Val Lys Asp Gly Leu Asn Gln Lys465 470 475 480Pro Glu Lys Gly Glu Asn Gly Ile Arg Phe Val Asn Thr Phe Asn Glu 485 490 495Leu Ile Thr Ile Thr Met Ser Gly Lys Val Tyr Ala Asn Ile Ser Ser 500 505 510Tyr Asn Ala Ser Thr Tyr Gln Phe Phe Pro Ser Gly Ile Lys Gly Phe 515 520 525Thr Ile Ser Ser Thr Glu Ile Pro Pro Gln Cys Gln Pro Asn Phe Asn 530 535 540Thr Phe Tyr Leu Glu Phe Gly Ser Ala Tyr Thr Tyr Ile Val Gln Arg545 550 555 560Lys Asn Asp Ser Cys Pro Glu Val Lys Val Phe Glu Asp Ile Ser Ala 565 570 575Asn Thr Val Asn Met Ala Leu Gln Ile Pro Gln Tyr Phe Leu Leu Thr 580 585 590Cys Gly Glu Val Val Phe Ser Val Thr Gly Leu Glu Phe Ser Tyr Ser 595 600 605Gln Ala Pro Ser Asn Met Lys Ser Val Leu Gln Ala Gly Trp Leu Leu 610 615 620Thr Val Ala Val Gly Asn Ile Ile Val Leu Ile Val Ala Gly Ala Gly625 630 635 640Gln Phe Ser Lys Gln Trp Ala Glu Tyr Ile Leu Phe Ala Ala Leu Leu 645 650 655Leu Val Val Cys Val Val Phe Ala Ile Met Ala Arg Phe Tyr Thr Tyr 660 665 670Ile Asn Pro Ala Glu Ile Glu Ala Gln Phe Asp Glu Asp Glu Lys Lys 675 680 685Asn Arg Leu Glu Lys Ser Asn Pro Tyr Phe Met Ser Gly Ala Asn Ser 690 695 700Gln Lys Gln Met705 17 44 PRT Artificial S15 44 mer fragment L-form 17Arg Ser Gly Ala Tyr Glu Ser Pro Asp Gly Arg Gly Gly Arg Ser Tyr1 5 10 15Val Gly Gly Gly Gly Gly Cys Gly Asn Ile Gly Arg Lys His Asn Leu 20 25 30Trp Gly Leu Arg Thr Ala Ser Pro Ala Cys Trp Asp 35 40 18 44 PRT Artificial S21 44 mer fragment L-form 18Ser Pro Arg Ser Phe Trp Pro Val Val Ser Arg His Glu Ser Phe Gly1 5 10 15Ile Ser Asn Tyr Leu Gly Cys Gly Tyr Arg Thr Cys Ile Ser Gly Thr 20 25 30Met Thr Lys Ser Ser Pro Ile Tyr Pro Arg His Ser 35 40 19 44 PRT Artificial S22 44 mer fragment L-form 19Ser Ser Ser Ser Asp Trp Gly Gly Val Pro Gly Lys Val Val Arg Glu1 5 10 15Arg Phe Lys Gly Arg Gly Cys Gly Ile Ser Ile Thr Ser Val Leu Thr 20 25 30Gly Lys Pro Asn Pro Cys Pro Glu Pro Lys Ala Ala 35 40 20 44 PRT Artificial Sni10 44 mer fragment L-form 20Arg Val Gly Gln Cys Thr Asp Ser Asp Val Arg Arg Pro Trp Ala Arg1 5 10 15Ser Cys Ala His Gln Gly Cys Gly Ala Gly Thr Arg Asn Ser His Gly 20 25 30Cys Ile Thr Arg Pro Leu Arg Gln Ala Ser Ala His 35 40 21 39 PRT Artificial Sni28 39 mer fragment L-form 21Ser His Ser Gly Gly Met Asn Arg Ala Tyr Gly Asp Val Phe Arg Glu1 5 10 15Leu Arg Asp Arg Trp Asn Ala Thr Ser His His Thr Arg Pro Thr Pro 20 25 30Gln Leu Pro Arg Gly Pro Asn 35 22 41 PRT Artificial Sni34 41 mer fragment L-form 22Ser Pro Cys Gly Gly Ser Trp Gly Arg Phe Met Gln Gly Gly Leu Phe1 5 10 15Gly Gly Arg Thr Asp Gly Cys Gly Ala His Arg Asn Arg Thr Ser Ala 20 25 30Ser Leu Glu Pro Pro Ser Ser Asp Tyr 35 40 23 39 PRT Artificial Sni38 39 mer fragment L-form 23Arg Gly Ala Ala Asp Gln Arg Arg Gly Trp Ser Glu Asn Leu Gly Leu1 5 10 15Pro Arg Val Gly Trp Asp Ala Ile Ala His Asn Ser Tyr Thr Phe Thr 20 25 30Ser Arg Arg Pro Arg Pro Pro 35 24 44 PRT Artificial Sni45 44 mer fragment L-form 24Ser Gly Gly Glu Val Ser Ser Trp Gly Arg Val Asn Asp Leu Cys Ala1 5 10 15Arg Val Ser Trp Thr Gly Cys Gly Thr Ala Arg Ser Ala Arg Thr Asp 20 25 30Asn Lys Gly Phe Leu Pro Lys His Ser Ser Leu Arg 35 40 25 44 PRT Artificial SniAX2 44 mer fragment L-form 25Ser Asp Ser Asp Gly Asp His Tyr Gly Leu Arg Gly Gly Val Arg Cys1 5 10 15Ser Leu Arg Asp Arg Gly Cys Gly Leu Ala Leu Ser Thr Val His Ala 20 25 30Gly Pro Pro Ser Phe Tyr Pro Lys Leu Ser Ser Pro 35 40 26 39 PRT Artificial SniAX4 39 mer fragment L-form 26Arg Ser Leu Gly Asn Tyr Gly Val Thr Gly Thr Val Asp Val Thr Val1 5 10 15Leu Pro Met Pro Gly His Ala Asn His Leu Gly Val Ser Ser Ala Ser 20 25 30Ser Ser Asp Pro Pro Arg Arg 35 27 38 PRT Artificial SniAX6 38 mer fragment L-form 27Arg Thr Thr Thr Ala Lys Gly Cys Leu Leu Gly Ser Phe Gly Val Leu1 5 10 15Ser Gly Cys Ser Phe Thr Pro Thr Ser Pro Pro Pro His Leu Gly Tyr 20 25 30Pro Pro His Ser Val Asn 35 28 39 PRT Artificial SniAX8 39 mer fragment L-form 28Ser Pro Lys Leu Ser Ser Val Gly Val Met Thr Lys Val Thr Glu Leu1 5 10 15Pro Thr Glu Gly Pro Asn Ala Ile Ser Ile Pro Ile Ser Ala Thr Leu 20 25 30Gly Pro Arg Asn Pro Leu Arg 35 29 39 PRT Artificial DAB3 39 mer fragment L-form 29Arg Trp Cys Gly Ala Glu Leu Cys Asn Ser Val Thr Lys Lys Phe Arg1 5 10 15Pro Gly Trp Arg Asp His Ala Asn Pro Ser Thr His His Arg Thr Pro 20 25 30Pro Pro Ser Gln Ser Ser Pro 35 30 44 PRT Artificial DAB7 44 mer fragment L-form 30Arg Trp Cys Gly Ala Asp Asp Pro Cys Gly Ala Ser Arg Trp Arg Gly1 5 10 15Gly Asn Ser Leu Phe Gly Cys Gly Leu Arg Cys Ser Ala Ala Gln Ser 20 25 30Thr Pro Ser Gly Arg Ile His Ser Thr Ser Thr Ser 35 40 31 39 PRT Artificial DAB10 39 mer fragment L-form 31Ser Lys Ser Gly Glu Gly Gly Asp Ser Ser Arg Gly Glu Thr Gly Trp1 5 10 15Ala Arg Val Arg Ser His Ala Met Thr Ala Gly Arg Phe Arg Trp Tyr 20 25 30Asn Gln Leu Pro Ser Asp Arg 35 32 38 PRT Artificial DAB18 38 mer fragment L-form 32Arg Ser Ser Ala Asn Asn Cys Glu Trp Lys Ser Asp Trp Met Arg Arg1 5 10 15Ala Cys Ile Ala Arg Tyr Ala Asn Ser Ser Gly Pro Ala Arg Ala Val 20 25 30Asp Thr Lys Ala Ala Pro 35 33 44 PRT Artificial DAB24 44 mer fragment L-form 33Ser Lys Trp Ser Trp Ser Ser Arg Trp Gly Ser Pro Gln Asp Lys Val1 5 10 15Glu Lys Thr Arg Ala Gly Cys Gly Gly Ser Pro Ser Ser Thr Asn Cys 20 25 30His Pro Tyr Thr Phe Ala Pro Pro Pro Gln Ala Gly 35 40 34 44 PRT Artificial DAB30 44 mer fragment L-form 34Ser Gly Phe Trp Glu Phe Ser Arg Gly Leu Trp Asp Gly Glu Asn Arg1 5 10 15Lys Ser Val Arg Ser Gly Cys Gly Phe Arg Gly Ser Ser Ala Gln Gly 20 25 30Pro Cys Pro Val Thr Pro Ala Thr Ile Asp Lys His 35 40 35 44 PRT Artificial DAX15 44 mer fragment L-form 35Ser Glu Ser Gly Arg Cys Arg Ser Val Ser Arg Trp Met Thr Thr Trp1 5 10 15Gln Thr Gln Lys Gly Gly Cys Gly Ser Asn Val Ser Arg Gly Ser Pro 20 25 30Leu Asp Pro Ser His Gln Thr Gly His Ala Thr Thr 35 40 36 39 PRT Artificial DAX23 39 mer fragment L-form 36Arg Glu Trp Arg Phe Ala Gly Pro Pro Leu Asp Leu Trp Ala Gly Pro1 5 10 15Ser Leu Pro Ser Phe Asn Ala Ser Ser His Pro Arg Ala Leu Arg Thr 20 25 30Tyr Trp Ser Gln Arg Pro Arg 35 37 44 PRT Artificial DAX24 44 mer fragment L-form 37Arg Met Glu Asp Ile Lys Asn Ser Gly Trp Arg Asp Ser Cys Arg Trp1 5 10 15Gly Asp Leu Arg Pro Gly Cys Gly Ser Arg Gln Trp Tyr Pro Ser Asn 20 25 30Met Arg Ser Ser Arg Asp Tyr Pro Ala Gly Gly His 35 40 38 36 PRT Artificial DAX27 36 mer fragment L-form 38Ser His Pro Trp Tyr Arg His Trp Asn His Gly Asp Phe Ser Gly Ser1 5 10 15Gly Gln Ser Arg His Thr Pro Pro Glu Ser Pro His Pro Gly Arg Pro 20 25 30Asn Ala Thr Ile 35 39 44 PRT Artificial DCX8 44 mer fragment L-form 39Arg Tyr Lys His Asp Ile Gly Cys Asp Ala Gly Val Asp Lys Lys Ser1 5 10 15Ser Ser Val Arg Gly Gly Cys Gly Ala His Ser Ser Pro Pro Arg Ala 20 25 30Gly Arg Gly Pro Arg Gly Thr Met Val Ser Arg Leu 35 40 40 44 PRT Artificial DCX11 44 mer fragment L-form 40Ser Gln Gly Ser Lys Gln Cys Met Gln Tyr Arg Thr Gly Arg Leu Thr1 5 10 15Val Gly Ser Glu Tyr Gly Cys Gly Met Asn Pro Ala Arg His Ala Thr 20 25 30Pro Ala Tyr Pro Ala Arg Leu Leu Pro Arg Tyr Arg 35 40 41 44 PRT Artificial DCX26 44 mer fragment L-form 41Ser Gly Arg Thr Thr Ser Glu Ile Ser Gly Leu Trp Gly Trp Gly Asp1 5 10 15Asp Arg Ser Gly Tyr Gly Trp Gly Asn Thr Leu Arg Pro Asn Tyr Ile 20 25 30Pro Tyr Arg Gln Ala Thr Asn Arg His Arg Tyr Thr 35 40 42 39 PRT Artificial DCX33 39 mer fragment L-form 42Arg Trp Asn Trp Thr Val Leu Pro Ala Thr Gly Gly His Tyr Trp Thr1 5 10 15Arg Ser Thr Asp Tyr His Ala Ile Asn Asn His Arg Pro Ser Ile Pro 20 25 30His Gln His Pro Thr Pro Ile 35 43 44 PRT Artificial DCX36 44 mer fragment L-form 43Ser Trp Ser Ser Trp Asn Trp Ser Ser Lys Thr Thr Arg Leu Gly Asp1 5 10 15Arg Ala Thr Arg Glu Gly Cys Gly Pro Ser Gln Ser Asp Gly Cys Pro 20 25 30Tyr Asn Gly Arg Leu Thr Thr Val Lys Pro Arg Thr 35 40 44 37 PRT Artificial DCX39 37 mer fragment L-form 44Ser Gly Ser Leu Asn Ala Trp Gln Pro Arg Ser Trp Val Gly Gly Ala1 5 10 15Phe Arg Ser His Ala Asn Asn Asn Leu Asn Pro Lys Pro Thr Met Val 20 25 30Thr Arg His Pro Thr 35 45 44 PRT Artificial DCX42 44 mer fragment L-form 45Arg Tyr Ser Gly Leu Ser Pro Arg Asp Asn Gly Pro Ala Cys Ser Gln1 5 10 15Glu Ala Thr Leu Glu Gly Cys Gly Ala Gln Arg Leu Met Ser Thr Arg 20 25 30Arg Lys Gly Arg Asn Ser Arg Pro Gly Trp Thr Leu 35 40 46 39 PRT Artificial DCX45 39 mer fragment L-form 46Ser Val Gly Asn Asp Lys Thr Ser Arg Pro Val Ser Phe Tyr Gly Arg1 5 10 15Val Ser Asp Leu Trp Asn Ala Ser Leu Met Pro Lys Arg Thr Pro Ser 20 25 30Ser Lys Arg His Asp Asp Gly 35 47 38 PRT Artificial PAX9 38 mer fragment L-form 47Arg Trp Pro Ser Val Gly Tyr Lys Gly Asn Gly Ser Asp Thr Ile Asp1 5 10 15Val His Ser Asn Asp Ala Ser Thr Lys Arg Ser Leu Ile Tyr Asn His 20 25 30Arg Arg Pro Leu Phe Pro 35 48 39 PRT Artificial PAX14 39 mer fragment L-form 48Arg Thr Phe Glu Asn Asp Gly Leu Gly Val Gly Arg Ser Ile Gln Lys1 5 10 15Lys Ser Asp Arg Trp Tyr Ala Ser His Asn Ile Arg Ser His Phe Ala 20 25 30Ser Met Ser Pro Ala Gly Lys 35 49 44 PRT Artificial PAX15 44 mer fragment L-form 49Ser Tyr Cys Arg Val Lys Gly Gly Gly Glu Gly Gly His Thr Asp Ser1 5 10 15Asn Leu Ala Arg Ser Gly Cys Gly Lys Val Ala Arg Thr Ser Arg Leu 20 25 30Gln His Ile Asn Pro Arg Ala Thr Pro Pro Ser Arg 35 40 50 39 PRT Artificial PAX16 39 mer fragment L-form 50Ser Trp Thr Arg Trp Gly Lys His Thr His Gly Gly Phe Val Asn Lys1 5 10 15Ser Pro Pro Gly Lys Asn Ala Thr Ser Pro Tyr Thr Asp Ala Gln Leu 20 25 30Pro Ser Asp Gln Gly Pro Pro 35 51 44 PRT Artificial PAX17 44 mer fragment L-form 51Ser Gln Val Asp Ser Phe Arg Asn Ser Phe Arg Trp Tyr Glu Pro Ser1 5 10 15Arg Ala Leu Cys His Gly Cys Gly Lys Arg Asp Thr Ser Thr Thr Arg 20 25 30Ile His Asn Ser Pro Ser Asp Ser Tyr Pro Thr Arg 35 40 52 39 PRT Artificial PAX18 39 mer fragment L-form 52Ser Phe Leu Arg Phe Gln Ser Pro Arg Phe Glu Asp Tyr Ser Arg Thr1 5 10 15Ile Ser Arg Leu Arg Asn Ala Thr Asn Pro Ser Asn Val Ser Asp Ala 20 25 30His Asn Asn Arg Ala Leu Ala 35 53 39 PRT Artificial PAX35 39 mer fragment L-form 53Arg Ser Ile Thr Asp Gly Gly Leu Asn Glu Val Asp Leu Ser Ser Val1 5 10 15Ser Asn Val Leu Glu Asn Ala Asn Ser His Arg Ala Tyr Arg Lys His 20 25 30Arg Pro Thr Leu Lys Arg Pro 35 54 44 PRT Artificial PAX38 44 mer fragment L-form 54Ser Ser Lys Val Ser Ser Pro Arg Asp Pro Thr Val Pro Arg Lys Gly1 5 10 15Gly Asn Val Asp Tyr Gly Cys Gly His Arg Ser Ser Ala Arg Met Pro 20 25 30Thr Ser Ala Leu Ser Ser Ile Thr Lys Cys Tyr Thr 35 40 55 44 PRT Artificial PAX40 44 mer fragment L-form 55Arg Ala Ser Thr Gln Gly Gly Arg Gly Val Ala Pro Glu Phe Gly Ala1 5 10 15Ser Val Leu Gly Arg Gly Cys Gly Ser Ala Thr Tyr Tyr Thr Asn Ser 20 25 30Thr Ser Cys Lys Asp Ala Met Gly His Asn Tyr Ser 35 40 56 39 PRT Artificial PAX43 39 mer fragment L-form 56Arg Trp Cys Glu Lys His Lys Phe Thr Ala Ala Arg Cys Ser Ala Gly1 5 10 15Ala Gly Phe Glu Arg Asp Ala Ser Arg Pro Pro Gln Pro Ala His Arg 20 25 30Asp Asn Thr Asn Arg Asn Ala 35 57 39 PRT Artificial PAX45 39 mer fragment L-form 57Ser Phe Gln Val Tyr Pro Asp His Gly Leu Glu Arg His Ala Leu Asp1 5 10 15Gly Thr Gly Pro Leu Tyr Ala Met Pro Gly Arg Trp Leu Arg Ala Arg 20 25 30Pro Gln Asn Arg Asp Arg Gln 35 58 38 PRT Artificial PAX46 38 mer fragment L-form 58Ser Arg Cys Thr Asp Asn Glu Gln Cys Pro Asp Thr Gly Thr Arg Ser1 5 10 15Arg Ser Val Ser Asn Ala Arg Tyr Phe Ser Ser Arg Leu Leu Lys Thr 20 25 30His Ala Pro His Arg Pro 35 59 39 PRT Artificial P31 39 mer fragment L-form 59Ser Ala Arg Asp Ser Gly Pro Ala Glu Asp Gly Ser Arg Ala Val Arg1 5 10 15Leu Asn Gly Val Glu Asn Ala Asn Thr Arg Lys Ser Ser Arg Ser Asn 20 25 30Pro Arg Gly Arg Arg His Pro 35 60 44 PRT Artificial P90 44 mer fragment L-form 60Ser Ser Ala Asp Ala Glu Lys Cys Ala Gly Ser Leu Leu Trp Trp Gly1 5 10 15Arg Gln Asn Asn Ser Gly Cys Gly Ser Pro Thr Lys Lys His Leu Lys 20 25 30His Arg Asn Arg Ser Gln Thr Ser Ser Ser Ser His 35 40 61 39 PRT Artificial 5PAX3 39 mer fragment L-form 61Arg Pro Lys Asn Val Ala Asp Ala Tyr Ser Ser Gln Asp Gly Ala Ala1 5 10 15Ala Glu Glu Thr Ser His Ala Ser Asn Ala Ala Arg Lys Ser Pro Lys 20 25 30His Lys Pro Leu Arg Arg Pro 35 62 39 PRT Artificial 5PAX5 39 mer fragment L-form 62Arg Gly Ser Thr Gly Thr Ala Gly Gly Glu Arg Ser Gly Val Leu Asn1 5 10 15Leu His Thr Arg Asp Asn Ala Ser Gly Ser Gly Phe Lys Pro Trp Tyr 20 25 30Pro Ser Asn Arg Gly His Lys 35 63 39 PRT Artificial 5PAX7 39 mer fragment L-form 63Arg Trp Gly Trp Glu Arg Ser Pro Ser Asp Tyr Asp Ser Asp Met Asp1 5 10 15Leu Gly Ala Arg Arg Tyr Ala Thr Arg Thr His Arg Ala Pro Pro Arg 20 25 30Val Leu Lys Ala Pro Leu Pro 35 64 44 PRT Artificial 5PAX12 44 mer fragment L-form 64Arg Gly Trp Lys Cys Glu Gly Ser Gln Ala Ala Tyr Gly Asp Lys Asp1 5 10 15Ile Gly Arg Ser Arg Gly Cys Gly Ser Ile Thr Lys Asn Asn Thr Asn 20 25 30His Ala His Pro Ser His Gly Ala Val Ala Lys Ile 35 40 65 39 PRT Artificial HAX9 39 mer fragment L-form 65Ser Arg Glu Glu Ala Asn Trp Asp Gly Tyr Lys Arg Glu Met Ser His1 5 10 15Arg Ser Arg Phe Trp Asp Ala Thr His Leu Ser Arg Pro Arg Arg Pro 20 25 30Ala Asn Ser Gly Asp Pro Asn 35 66 44 PRT Artificial HAX35 44 mer fragment L-form 66Glu Trp Tyr Ser Trp Lys Arg Ser Ser Lys Ser Thr Gly Leu Gly Asp1 5 10 15Thr Ala Thr Arg Glu Gly Cys Gly Pro Ser Gln Ser Asp Gly Cys Pro 20 25 30Tyr Asn Gly Arg Leu Thr Thr Val Lys Pro Arg Lys 35 40 67 44 PRT Artificial HAX40 44 mer fragment L-form 67Arg Glu Phe Ala Glu Arg Arg Leu Trp Gly Cys Asp Asp Leu Ser Trp1 5 10 15Arg Leu Asp Ala Glu Gly Cys Gly Pro Thr Pro Ser Asn Arg Ala Val 20 25 30Lys His Arg Lys Pro Arg Pro Arg Ser Pro Ala Leu 35 40 68 44 PRT Artificial HAX42 44 mer fragment L-form 68Ser Asp His Ala Leu Gly Thr Asn Leu Arg Ser Asp Asn Ala Lys Glu1 5 10 15Pro Gly Asp Tyr Asn Cys Cys Gly Asn Gly Asn Ser Thr Gly Arg Lys 20 25 30Val Phe Asn Arg Arg Arg Pro Ser Ala Ile Pro Thr 35 40 69 44 PRT Artificial HCA3 44 mer fragment L-form 69Arg His Ile Ser Glu Tyr Ser Phe Ala Asn Ser His Leu Met Gly Gly1 5 10 15Glu Ser Lys Arg Lys Gly Cys Gly Ile Asn Gly Ser Phe Ser Pro Thr 20 25 30Cys Pro Arg Ser Pro Thr Pro Ala Phe Arg Arg Thr 35 40 70 38 PRT Artificial H40 38 mer fragment L-form 70Ser Arg Glu Ser Gly Met Trp Gly Ser Trp Trp Arg Gly His Arg Leu1 5 10 15Asn Ser Thr Gly Gly Asn Ala Asn Met Asn Ala Ser Leu Pro Pro Asp 20 25 30Pro Pro Val Ser Thr Pro 35 71 39 PRT Artificial PAX2 39 mer fragment L-form 71Ser Thr Pro Pro Ser Arg Glu Ala Tyr Ser Arg Pro Tyr Ser Val Asp1 5 10 15Ser Asp Ser Asp Thr Asn Ala Lys His Ser Ser His Asn Arg Arg Leu 20 25 30Arg Thr Arg Ser Arg Pro Asn 35 72 11 PRT Artificial binding 11 mer fragment L-form 72Xaa Thr Xaa Xaa Ser Xaa Xaa Xaa Asn Xaa Arg1 5 10 73 8 PRT Artificial binding 8 mer fragment L-form 73Asp Xaa Asp Xaa Arg Arg Xaa Xaa1 5 74 10 PRT Artificial binding 10 mer fragment L-form 74Val Arg Ser Gly Cys Gly Xaa Xaa Ser Ser1 5 10 75 11 PRT Artificial binding 11 mer fragment L-form 75Asn Thr Arg Lys Ser Ser Arg Ser Asn Pro Arg1 5 10 76 11 PRT Artificial binding 11 mer fragment L-form 76Ser Thr Lys Arg Ser Leu Ile Tyr Asn His Arg1 5 10 77 10 PRT Artificial binding 10 mer fragment L-form 77Ser Thr Gly Arg Lys Val Phe Asn Arg Arg1 5 10 78 11 PRT Artificial binding 11 mer fragment L-form 78Thr Asn Ala Lys His Ser Ser His Asn Arg Arg1 5 10 79 8 PRT Artificial binding 8 mer fragment L-form 79Asp Ser Asp Val Arg Arg Pro Trp1 5 80 8 PRT Artificial binding 8 mer fragment L-form 80Ala Ala Asp Gln Arg Arg Gly Trp1 5 81 8 PRT Artificial binding 8 mer fragment L-form 81Asp Gly Arg Gly Gly Arg Ser Tyr1 5 82 4 PRT Artificial binding 4 mer fragment L-form 82Arg Val Arg Ser1 83 12 PRT Artificial binding 12 mer fragment L-form 83Ser Val Arg Ser Gly Cys Gly Phe Arg Gly Ser Ser1 5 10 84 11 PRT Artificial binding 11 mer fragment L-form 84Ser Val Arg Gly Gly Cys Gly Ala His Ser Ser1 5 10

Claims

1. An isolated antibody or antibody fragment specific to a domain of a gastro-intestinal tract (GIT) targeting agent, said targeting agent comprising ZElan033 (PAX2 15 mer) (SEQ ID NO:1).

2. The antibody or antibody fragment of claim 1, wherein the antibody or antibody fragment is selected from the group consisting of a polyclonal antibody, monoclonal antibody, chimeric antibody, single chain antibody, a Fab fragment or a Fab expression library.