Isolated nucleic acid molecules which are members of the MAGE-B family and uses thereof

The invention relates to members of the MAGE-B family of nucleic acid molecules. These molecules differ from the previously described MAGE nucleic acid molecules in that members of the MAGE-Xp family do not hybridize to the previously identified MAGE sequences. Further, the members of the MAGE-B family are found on the Xp arm of the X chromosome rather than on the Xq chromosome, as was the case with the previously identified MASGE genes.

FIELD OF THE INVENTION 
This invention relates to a nucleic acid molecule which codes for a tumor 
rejection antigen precursor. More particularly, the invention concerns 
genes, whose tumor rejection antigen precursor is processed, inter alia, 
into at least one tumor rejection antigen. The tumor rejection antigen 
precursors in question do not appear to be closely related to other known 
tumor rejection antigen precursor coding sequences, and were isolated from 
the Xp region of human X chromosones, in contrast to the genes to which 
they are most closely related, which were found on the Xq region. These 
newly isolated genes are members of the MAGE-B family, while those in the 
Xq region are now considered to be members of the MAGE-A family. 
BACKGROUND AND PRIOR ART 
The process by which the mammalian immune system recognizes and reacts to 
foreign or alien materials is a complex one. An important facet of the 
system is the T lymphocyte, or "T cell" response. This response requires 
that T cells recognize and interact with complexes of cell surface 
molecules, referred to as human leukocyte antigens ("HLA"), or major 
histocompatibilty complexes ("MHCs"), and peptides, The peptides are 
derived from larger molecules which are processed by the cells which also 
present the HLA/MHC molecule. See in this regard Male et al., Advanced 
Immunology (J. P. Lippincott Company, 1987), especially chapters 6-10. The 
interaction of T cells and HLA/peptide complexes is restricted, requiring 
a T cell specific for a particular combination of an HLA molecule and a 
peptide, If a specific T cell is not present, there is no T cell response 
even if its partner complex is present. Similarly, there is no response if 
the specific complex is absent, but the T cell is present. This mechanism 
is involved in the immune system's response to foreign materials, in 
autoimmune pathologies, and in responses to cellular abnormalities. Much 
work has focused on the mechanisms by which proteins are processed into 
the HLA binding peptides. See, in this regard, Barinaga, Science 257:880 
(1992); Fremont et al., Science 257:919 (1992); Matsumura et al,m Science 
257:927 (1992); Latron et al., Science 257:964 (1992). 
The mechanism by which T cells recognize cellular abnormalities has also 
been implicated in cancer, For example, in PCT application PCT/US92/04354, 
filed May 22, 1992, published on Nov. 26, 1992, and incorporated by 
reference, a family of genes is disclosed, which are processed into 
peptides which, in turn, are expressed on cell surfaces, which can lead to 
lysis of the tumor cells by specific CTLs cytolytic T lymphocytes, or 
"CTLs" hereafter. The genes are said to code for "tumor rejection antigen 
precursors" or "TRAP" molecules, and the peptides derived therefrom are 
referred to as "tumor rejection antigens" or "TRAs". See Traversari et 
al., Immunogenetics 35:145 (1992); van der Bruggen et al., Science 
254:1643 (1991), for further information on this family of genes. Also, 
see U.S. patent application Ser. No. 807,043, filed Dec. 12, 1991, now 
U.S. Pat. No. 5,342,774, incorporated by reference in its entirety. The 
"MAGE" family of tumor rejection antigen precursors is disclosed in this 
patent. 
In U.S. patent application Ser. No. 938,334, now U.S. Pat. No. 5,405,940 
Apr. 15, 1995, the disclosure of which is incorporated by reference, it is 
explained that the MAGE-1 gene codes for a tumor rejection antigen 
precursor which is processed to nonapeptides which are presented by the 
HLA-A1 molecule. The nonapeptides which bind to HLA-A1 follow a "rule" for 
binding in that a motif is satisfied. In this regard, see e.g. 
PCT/US93/07421; Falk et al., Nature 351: 290-296 (1991); Engelhard, Ann 
Rev. Immunol. 12: 181-207 (1994); Ruppert et al., Cell 74: 929-937 (1993); 
Rotzchke et al, Nature 348: 252-254 (1990); Bjorkman et al., Nature 329: 
512-518 (1987); Traversari et al., J. Exp. Med. 176: 1453-1457 (1992). The 
references teach that given the known specificity of particular peptides 
for particular HLA molecules, one should expect a particular peptide to 
bind to one HLA molecule, but not to others. This is important, because 
different individuals possess different HLA phenotypes. As a result, while 
identification of a particular peptide as being a partner for a specific 
HLA molecule has diagnostic and therapeutic ramifications, these are only 
relevant for individuals with that particular HLA phenotype. There is a 
need for further work in the area, because cellular abnormalities are not 
restricted to one particular HLA phenotype, and targeted therapy requires 
some knowledge fo the phenotype of the abnormal cells at issue. 
In U.S. Pat. application Ser. No. 008,446, filed Jan. 22, 1993 now U.S. 
Pat. No. 5,885,165, and incorporated by reference, the fact that the 
MAGE-1 expression product is processed to a second TRA is disclosed. This 
second TRA is present by HLA-Cw*1601 molecules. The disclosure shows that 
a given TRAP can yield a plurality of TRAs, each of which will satisfy a 
motif rule for binding to an MHC molecule. 
In U.S. Pat. application Ser. No. 994,928, filed Dec. 22, 1992, now 
abandoned, and incorporated by reference herein teaches that tyrosinase, a 
molecule which is produced by some normal cells (e.g., melanocytes), is 
processed in tumor cells to yield peptides presented by HLA-A2 molecules. 
In U.S. patent applciation Ser. No. 08/032,978, filed Mar. 18, 1993, now 
U.S. Pat. No. 5,620,886, and incorporated by reference in its entirety, a 
second TRA, not derived from tyrosinase is taught to be presented by 
HLA-A2 molecules. The TRA is derived from a TRAP, but is coded for by a 
non-MAGE gene. This disclosure shows that a particular HLA molecule may 
present TRAs derived from different sources. 
In U.S. patent application Ser. No. 08/079,110, now U.S. Pat. No. 
5,571,711, filed Jun. 17, 1993 and incorporated by reference herein, an 
unrelated tumor rejection antigen precursor, the so-called "BAGE" 
precursor is described. The BAGE precursor is not related to the MAGE 
family. 
In U.S. patent applications Ser. No. 08/096,039, now abandoned, and Ser. 
No. 08/250,162, now U.S. Pat. No. 5,610,013, both of which are 
incorporated by reference, non-related TRAP precursor GAGE is also 
disclosed. 
The work which is presented by the papers, patent, and patent applications 
cited supra deal, in large part, with the MAGE family of genes, and the 
unrelated BAGE, GAGE and DAGE genes, showing that there are different, 
additional tumor rejection antigen precursors expressed by cells. 
It has now been found that there is yet another family of tumor rejection 
antigen precursor genes. These nucleic acid molecules show homology to the 
MAGE family of genes, but this homology is insufficient to identify the 
members of the MAGE-B family by hybridization with the members of the 
MAGE-A family, as set forth in, e.g., PCT Application PCT/US92/04354 and 
U.S. Pat. No. 5,342,774, under the conditions of stringency set forth 
therein. Further, the isolated nucleic acid molecules of the invention 
were all found on the Xp arm of the X chromosome, as contrasted to the 
previously identified members of the MAGE-A family, all of which were 
found on the Xq are, Thus, the invention relates to isolated nucleic acid 
molecules which encode for MAGE-B tumor rejection antigen precursors and 
the uses thereof. 
The invention is explained in further detail in the disclosure which 
follows. 
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS