GPA33

Official Full Name

glycoprotein A33

Organism

Homo sapiens

GeneID

10223

Background

The glycoprotein encoded by this gene is a cell surface antigen that is expressed in greater than 95% of human colon cancers. The open reading frame encodes a 319-amino acid polypeptide having a putative secretory signal sequence and 3 potential glycosylation sites. The predicted mature protein has a 213-amino acid extracellular region, a single transmembrane domain, and a 62-amino acid intracellular tail. The sequence of the extracellular region contains 2 domains characteristic of the CD2 subgroup of the immunoglobulin (Ig) superfamily. [provided by RefSeq, Jul 2008]

Synonyms

A33;

Bio Chemical Class

Immunoglobulin

Protein Sequence

MVGKMWPVLWTLCAVRVTVDAISVETPQDVLRASQGKSVTLPCTYHTSTSSREGLIQWDKLLLTHTERVVIWPFSNKNYIHGELYKNRVSISNNAEQSDASITIDQLTMADNGTYECSVSLMSDLEGNTKSRVRLLVLVPPSKPECGIEGETIIGNNIQLTCQSKEGSPTPQYSWKRYNILNQEQPLAQPASGQPVSLKNISTDTSGYYICTSSNEEGTQFCNITVAVRSPSMNVALYVGIAVGVVAALIIIGIIIYCCCCRGKDDNTEDKEDARPNREAYEEPPEQLRELSREREEEDDYRQEEQRSTGRESPDHLDQ

Open

Disease

Colorectal cancer

Approved Drug

Clinical Trial Drug

4 +

Discontinued Drug

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Detailed Information

Belonging to the immunoglobulin (Ig) superfamily, glycoprotein A33 (GPA33) is a cell surface antigen that is very important for cell-cell interaction and communication. Particularly in both primary and metastatic colorectal cancers (CRC), approximately 95% of human colon tumors are strongly expressed. Though not in normal gastric epithelium, GPA33 is present in around 55% of gastric malignancies. Comprising a 213-amino acid extracellular region, a single transmembrane domain, and a 62-amino acid intracellular tail, the GPA33 gene produces a 319-amino acid glycoprotein. Characteristic of the CD2 subgroup of the Ig superfamily, the extracellular region has two Ig-like domains that are especially important for immunological regulation and cell adhesion.

GPA33's structure is also sensitive to post-translational changes like N-glycosylation and S-palmitoylation and has possible glycosylation sites. These changes could affect the internalization of the antigen when it interacts with monoclonal antibodies targeting GPA33. Especially in the framework of immunotherapy, the high expression of GPA33 in CRC and its correlation with tumor cells make it a desirable target for cancer treatment.

Figure 1 illustrates the structure of GPA33, highlighting its key components. Figure 1. Structure of GPA33.

GPA33 as a Target for Cancer Immunotherapy

Particularly CRC, GPA33 has attracted much interest as a possible target for immunotherapy in gastrointestinal cancers. More specifically, it is a particular marker for CRC exhibiting comparable sensitivity to CDX2. GPA33 is a good candidate for diagnostic and therapeutic targeting as it specifically expresses in tumor tissues rather than in normal tissue.

Several clinical studies have started for medications aiming at GPA33. Developed by Kyowa Kirin, KRN330 is a completely human monoclonal antibody. KRN330 was tested in a Phase I/II clinical study for the treatment of metastatic CRC (mCRC) when coupled with irinotecan. The experiment was stopped in 2015, nevertheless, since it did not satisfy the established objective response rate (ORR) requirements. Targeting GPA33, another important medication is MGD007, a bispecific antibody targeting CD3 as well as GPA33. MacroGenics created MGD007 to be used with the DART (Dual-Affinity Re-Targeting) technology platform. Especially when coupled with PD-1 inhibitors, such as MGA012, clinical studies have shown MGD007's promise. This combination has shown encouraging outcomes in terms of T-cell redirection and enhanced tumor cell killing in Phase I/II clinical trials for refractory or metastatic CRC.

Though they have presented some difficulties, including the diversity in GPA33 expression and different treatment responses, these GPA33-targeting medicines nevertheless inspire further study. Particularly, the creation of radiolabeled antibody medications, like 131I-huA33, seems promising when combined with chemotherapy, such as Capecitabine, and may enhance treatment results. Furthermore, a stepwise drug delivery technique called pre-targeting radioimmunotherapy (PRIT) might improve the efficacy of these therapies by providing more time for the radiolabeled antibodies to gather at the tumor location before administering the radioactive isotopes.

Recent Developments and Challenges in GPA33-Based Therapies

GPA33 expression in various cancers varies, which complicates the creation of GPA33-targeted treatments. Rightly identifying GPA33-positive, well-differentiated tumors before therapy should help these treatments work better. Though antibodies aimed against GPA33 have shown efficient tumor cell death in preclinical research, their therapeutic effectiveness is still limited. Recent research indicates that finding high GPA33 expression might increase the specificity of therapies and lower off-target effects, hence possibly boosting therapeutic results.

Moreover, GPA33 has a role in the detection of tTreg, or thymus-derived regulatory T cells, which are important in the immunological setting of CRC. GPA33's high expression in tTreg cells has been linked to lower inflammatory cytokine generation, hence supporting the use of GPA33-targeted treatments in adoptive tTreg cell therapy for CRC.

GPA33-targeted treatments continue to be the subject of constant study despite the difficulties they encounter in clinical trials. To improve their anti-tumor effects, there is increasing interest in combining GPA33-targeting monoclonal antibodies with other immune-based therapies such as immune checkpoint inhibitors. More study gives optimism that future novel and more potent medications aimed at GPA33 may surface.

Conclusion

GPA33 is a promising target for immunotherapy, particularly in colorectal and gastric cancers. Its particular expression patterns and significant presence in cancer tissues suggest it could be a candidate for targeted therapies. GPA33-targeted therapy's clinical development has been both promising and difficult. The future path of GPA33-targeted cancer immunotherapy is represented by drugs like MGD007, which employ creative technologies such as bispecific antibodies and T-cell redirection. More study, meantime, is required to handle the diversity of GPA33 expression in malignancies and maximize therapeutic approaches. GPA33 may be a main target in the battle against gastrointestinal cancers with ongoing research and creativity, hence providing fresh hope for CRC patients as well as other connected cancers.

References:

Opstelten R, Suwandi JS, Slot MC, et al. GPA33 is expressed on multiple human blood cell types and distinguishes CD4+ central memory T cells with and without effector function. Eur J Immunol. 2021;51(6):1377-1389.
Chopra A. Radioiodinated humanized monoclonal antibody A33. In: Molecular Imaging and Contrast Agent Database (MICAD). Bethesda (MD): National Center for Biotechnology Information (US); September 16, 2007.

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