Antigenic epitopes with Lym-1 reactivity and uses thereof

Details Antigenic epitopes with Lym-1 reactivity and uses thereof Antigenic epitopes with Lym-1 reactivity and uses thereof

2001-04-10

2004-08-31

Huff, Sheela J. (Department: 1642)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

C435S975000

Reexamination Certificate

active

06783936

ABSTRACT:

FIELD OF THE INVENTION
This invention has identified novel peptide epitopes recognized by the B cell lymphoma-reactive Lym-1 antibody. Because Lym-1 specifically reacts with non-Hodgkin's B cell lymphoma cells, the invention provides an improved, accurate means to identify cancer patients potentially responsive to Lym-1 antibody used as a cytotoxic therapeutic reagent. The invention also provides methods of generating antibodies directed against non-Hodgkin's B cell lymphoma cells which can be used in the treatment of non-Hodgkin's B cell lymphoma.
INTRODUCTION
Low grade B-cell non-Hodgkin's lymphomas (B-NHL) represent a markedly heterogeneous group of lymphoproliferative disorders (Gaidano (1997) Leuk. Lymphoma 26 Suppl. 1:107-113; Gandini (1996) Cancer Genet Cytogenet. 86:120-123). A widely used treatment for these lymphomas involves administration of a B-NHL-specific antibody, called Lym-1. Lym-1 is a murine IgG
2a
monoclonal antibody. When conjugated to cytotoxic agents, Lym-1 targets and kills B-NHL lymphoma cells (see, e.g., Rose (1996) Cancer Immunol. Immunother. 43:26-30; Epstein (1987) Cancer Res. 47:830-840). Lym-1 has been radiolabeled with
131
I (see, e.g., DeNardo (1997) Cancer 80:2706-2711) and conjugated to the ribosome inactivating protein gelonin (see, e.g., O'Boyle (1995) J. Immunother. Emphasis Tumor Immunol. 18:221-230). However, these reagents are inherently toxic, and not all B-NHL patients have Lym-1 reactive cancer cells. Thus, there is a need for a means to identify which patients will be responsive to such immunotherapy. Wile Lym-1 binding is associated with the expression of HLA DR10 by a patient, unfortunately, the absence of DR10, does not consistently correlate with the presence or absence of the Lym-1 reactive epitope. In another words, Lym-1 can react with HLA DR molecules other than DR10. Thus, there is a great need for a means to quickly, efficiently, and accurately determine the presence of a Lym-1 reactive epitope in a B-NHL cancer patient. The present invention, which for the first time identifies Lym-1 reactive peptide epitopes, fulfills these and other needs.
Typically, no immune response is generated by the cancer patient against B-NHL cells. However, based on studies with other tumor specific antigens (e.g., PSA antigen in prostate cancer), identification of an immunogenic peptide, followed by its administration with adjuvant, can elicit a tumor-specific immune response (see, e.g., Correale (1998) J. Immunol. 161:3186-3194). See also, Gjertsen (1998) Vox Sang. 74 Suppl 2:489-495, who uses an immunogenic peptide from a carcinogenic, mutant ras polypeptide to generate an immune response to pancreatic- and colorectal adenocarcinomas. The present invention, by identifying Lym-1 reactive epitopes on B-NHL cells, provides such a therapeutic immunogenic peptide.
SUMMARY OF THE INVENTION
The invention for the first time provides a composition comprising an isolated or recombinant peptide comprising a subsequence of a Class II major histocompatibility molecule that generates an immune response to a non-Hodgkin's B cell lymphoma cell. The peptide of the invention has a structure comprising R
1
-R
2
-R
3
-R
4
-R
5
-R
6
-R
7
-R
8
-R
9
-R
10
-R
11
-R
12
-R
13
-R
14
-R
15
-R
16
, wherein R
1
is Gln, Lys, or Arg; R
2
is Arg; R
3
and R
4
are members independently selected from the group consisting of all amino acids; R
5
is Ala, Glu, Asp, Val, Leu or Ile; R
6
and R
7
are members independently selected from the group consisting of all amino acids; R
8
is Thr; R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, and R
15
are members independently selected from the group consisting of all amino acids; and, R
16
is Val.
In one embodiment, the peptide of the invention has a structure wherein R
1
is Gln, Lys, or Arg; R
2
is Arg; R
3
is Arg; R
4
is selected from the group consisting of all amino acids; R
5
is Ala; R
6
and R
7
are members independently selected from the group consisting of all amino acids; R
8
is Thr; R
9
is selected from the group consisting of all amino acids; R
10
is Cys; R
11
, R
12
, R
13
, R
14
, and R
15
are members independently selected from the group consisting of all amino acids; and, R
16
is Val (SEQ ID NO:1). In a preferred embodiment, the immunogenic peptide comprises a structure wherein R
1
is Gln, Lys, or Arg; R
2
is Arg; R
3
is Arg; R
4
is Ala; R, is Ala; R
6
is Val; R
7
is Asp; R
8
is Thr; R
9
is Tyr; R
10
is Cys; R
11
is Arg; R
12
is His; R
13
is Asn; R
14
is Tyr; R
15
is Gly, and R
16
is Val (SEQ ID NO:2).
In alternative embodiments, the composition further comprises a pharmaceutically acceptable excipient and an adjuvant.
The composition of the invention can generate an immune response to a non-Hodgkin's lymphoma cell (B-NHL), including, e.g., a B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CCL/SLL) cell, a lymphoplasmacytoid lymphoma (LPL) cell, a follicular lymphoma (FL) cell, a mucosa-associated lymphoid tissue lymphoma (MALTL) cell, a splenic lymphoma with villous lymphocytes (SLVL) cell and a mantle cell lymphoma cell.
The invention also provides a method for detecting a nucleic acid in a biological sample, wherein the nucleic acid encodes a peptide capable of specifically binding to a Lym-1 antibody. The method of the invention comprises contacting the sample with an oligonucleotide primer pair capable of amplifying a subsequence of an MHC nucleic acid, which subsequence encodes a polypeptide comprising a peptide of the invention, as described above; amplifying the nucleic acid; and, detecting the amplified nucleic acid. In alternative embodiments, the MHC gene is HLA-DR 10 and the subsequence encodes a peptide wherein R
1
is Gin, Lys, or Arg; R
2
is Arg; R
3
is Arg; R
4
is Ala; R
5
is Ala; R
6
is Val; R
7
is Asp; R
8
is Thr; R
9
is Tyr; R
10
is Cys; R
11
is Arg; R
12
is His; R
13
is Asn; R
14
is Tyr; R
15
is Gly, and R
16
is Val (SEQ ID NO:2).
In the methods, the biological sample can comprise a B cell, or specifically, a B lymphocytic non-Hodgkin's lymphoma cell (B-NHL). The B-NHL cell can be a B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CCL/SLL) cell, a lymphoplasmacytoid lymphoma (LPL) cell, a follicular lymphoma (FL) cell, a mucosa-associated lymphoid tissue lymphoma (MALTL) cell, a splenic lymphoma with villous lymphocytes (SLVL) cell and a mantle cell lymphoma cell. In alternative embodiments the biological sample can be a body fluid sample or a biopsy sample; and the body fluid sample can be a blood sample.
The invention further provides a kit for detecting a nucleic acid in a biological sample, wherein the nucleic acid encodes a peptide capable of specifically binding to a Lym-1 antibody. The kit comprises an oligonucleotide primer pair capable of amplifying a subsequence of an MHC gene or gene product, which subsequence encodes a polypeptide comprising a peptide of the invention. In alternative embodiments, the MHC gene can be HLA-DR 10; and, the peptide can comprise a structure wherein R
1
is Gin, Lys, or Arg; R
2
is Arg; R
3
is Arg; R
4
is Ala; R
5
is Ala; R
6
is Val; R
7
is Asp; R
8
is Thr; R
9
is Tyr; R
10
is Cys; R
11
is Arg; R
12
is His; R
13
is Asn; R
14
is Tyr; R
15
is Gly, and R
16
is Val (SEQ ID NO:2).
In another embodiment, the kit of the invention can further comprise an instructional material teaching a use of the kit, wherein the instructional material indicates that the kit is used for the detection of nucleic acid encoding a peptide reactive with a Lym-1 antibody and that the polypeptide is associated with non-Hodgkin's B cell lymphomas.
The invention also provides a method for detecting an antibody reactive with a non-Hodgkin's B cell lymphoma (B-NHL) cell. The method comprises contacting a sample, which can be a biological sample, with a composition of the invention under immunologically reactive conditions, and then detecting whether an antibody has specifically bound to the composition. In one embodiment, the composition comprises a pepti

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