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HA-1 epitopes and uses thereof

a technology of ha1 and epitope, applied in the field of biotechnology, can solve the problems of not being able to identify amino acids, and no one has succeeded in identification

Inactive Publication Date: 2008-08-28
GOULMY ELSA A J M +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0023]An HA-1-negative donor for bone marrow transplantation can be vaccinated with a peptide of the invention, i.e., an HA-1 peptide. Upon transplantation to an HA-1-positive recipient, the donor's immune system eliminates residual or recurrent HA-1 peptide-presenting cells in the recipient, which are, of course, leukemic or non-hematopoietic tumor cells. This is another example of tailor-made adoptive immunotherapy provided herein.
[0090]In one embodiment, T-cells of the invention are provided comprising additional features. Such additional features, for instance, comprise safety features, or additional (co)-stimulation features. Safety is, for instance, built in using so-called suicide genes. Additionally, other features can be built in, like, for instance, features to improve anti-tumor effect of grafted T-cells.

Problems solved by technology

However, until the invention hereof, no one has succeeded in identifying amino acid sequences of antigenic peptides relevant to the mHag HA-1 antigen, nor has anyone succeeded in the identification of the proteins from which this antigen is derived.

Method used

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  • HA-1 epitopes and uses thereof

Examples

Experimental program
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example 1

[0115]GvHD is a frequent and life-threatening complication after allogeneic HLA-identical bone marrow transplantation (BMT). Recipients of HLA-identical bone marrow develop acute or chronic GvHD in respectively 36% and 49%.1, 2 Disparities in genes other than the MHC, referred to as minor histocompatibility antigens (mHags), are clearly involved in the development of GvHD after HLA-identical BMT. A recent retrospective analysis revealed the significant association between mismatching for the mHag HA-1 and the induction of GvHD after HLA-identical BMT.3 mHags are recognized by MHC restricted T-cells and were shown to be peptides derived from intracellular proteins presented by MHC molecules.4-6 Here we report the first identification of a polymorphic gene encoding an human mHag. The GvHD-associated mHag HA-1 is a nonapeptide derived from the di-allelic KIAA0223 gene. The HA-1 allelic counterpart encoded by the KIAA0223 gene differs only at one amino acid from the mHag HA-1. Family st...

example 2

[0151]To confirm the hematopoietic system restricted tissue distribution, earlier analyzed by HA-1-specific CTLs, HA-1 mRNA levels were analyzed by quantitative real-time PCR (Example 4) in eight different hematopoietic and six different non-hematopoietic cell types. Only cells of hematopoietic origin expressed significant levels of the HA-1 gene (FIG. 8). No significant HA-1 gene expression was detected in cells of non-hematopoietic origin: i.e., keratinocytes, dermal fibroblasts, proximal tubular epithelial cells (PTECs), human umbilical vein endothelial cells (HUVECs), melanocytes and SV 40 immortalized breast cell lines HaCaT and HBL 100 (FIG. 8).

[0152]Next, we investigated the HA-1 gene transcription levels in 35 epithelial tumor cell lines derived from different carcinomas (Table 1). The HA-1 gene transcription, analyzed by quantitative real time RT-PCR, revealed significant HA-1 mRNA in 26 out of the 35 cell lines of various malignant origins. Table 1 also lists the results o...

example 3

[0156]We have investigated whether the HA-1H / R polymorphic region contains peptides that can be presented by other HLA molecules than HLA-A2. Hereto, we analyzed the binding capacities of HA-1 polymorphic peptides to nine HLA-A and -B molecules that have a frequency of more than 10% in the Caucasian population. Nonameric HA-1H / R peptides (n=18) were tested for binding to these frequent HLA alleles. The peptide binding analyses were extended with two decameric HA-1H / R peptides that contained binding motives for HLA-A3 and with five nonameric / decameric peptides that were predicted to bind to HLA-B14 or to -B60. Next to the binding studies, cellular processing was executed by in vitro proteasome digestion of 29 amino acid long HA-1H and HA-1R peptides. To enlarge the patient population for HA-1-specific immunotherapy, the HLA-B60 binding peptides were analyzed for their in vitro immunizing potential. Hereto, peptide loaded dendritic cells (DCs) were used to induce T-cell responses from...

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Abstract

Peptide sequences constituting T-cell epitopes of minor Histocompatibility antigen, HA-1. HA-1 is associated with Graft versus Host Disease. The peptides and their derivatives find many uses, for instance, in bone marrow transplantation, organ transplantation and in treatment of leukemia and non-hematopoietic tumors. The peptide and / or its derivatives can be incorporated in vaccines, in pharmaceutical formulations and they can be used in diagnostic test kits. HA-1 is expressed by non-hematopoietic tumor cells. While absent in normal epithelial cells, tumor cells and tumor cell lines, particularly from epithelial origin, express HA-1 and are recognized by HA-1 cytotoxic T-cells. The invention provides means and methods for HA-1 specific immunotherapy for HA-1-positive patients with non-hematopoietic tumor cells.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of co-pending U.S. patent application Ser. No. 10 / 623,176, filed Jul. 18, 2003, which application is a continuation in part of co-pending application U.S. Ser. No. 09 / 489,760, filed on Jan. 21, 2000, the contents of the entirety of each of which are incorporated herein by this reference.STATEMENT ACCORDING TO 37 C.F.R. §1.52(e)(5) -SEQUENCE LISTING SUBMITTED ON COMPACT DISC[0002]Pursuant to 37 C.F.R. §1.52(e)(1)(iii), a compact disc containing an electronic version of the Sequence Listing has been submitted concomitant with this application, the contents of which are hereby incorporated by reference. A second compact disc is submitted and is an identical copy of the first compact disc. The discs are labeled “copy 1” and “copy 2,” respectively, and each disc contains one file entitled “2183-6047 seq list.txt” which is 35 KB and created on Jan. 9, 2006.TECHNICAL FIELD[0003]The invention relates generally t...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/00C07K7/06A61K38/08A61P31/00C07K16/00A61K35/14C12N5/10A61K38/00A61K38/17A61P35/02A61P37/06C07K14/705C07K14/74C07K16/28C12N5/07C12N5/0781C12N5/0783C12N5/09C12Q1/68
CPCA61K39/00C07K14/70539C07K7/06A61K2039/5154A61P31/00A61P35/02A61P37/06
Inventor GOULMY, ELSA A.J.M.HUNT, DONALD F.ENGELHARD, VICTOR H.
Owner GOULMY ELSA A J M
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