Disease relevance of LY6D

• The human E48 Ag was originally identified as a target Ag for radioimmunotherapy of patients with squamous cell carcinoma [1].
• Significantly, the E48 antigen, associated with poor metastasis-free survival in head and neck cancer, was identified as one specific target of TF 20-VP [2].
• After immunization of mice with viable cells of a metastasis of a laryngeal squamous cell carcinoma, a monoclonal antibody E 48 was obtained that detects an epitope present exclusively in squamous and transitional epithelium and their neoplastic counterparts [3].
• The E 48 antigen, which is formaldehyde resistant, appears to be a reliable marker for differentiation of squamous cell carcinomas from adenocarcinoma, and small cell carcinomas [3].
• Ten of the 13 bladder carcinomas expressed E48; all prostatic tumours were totally negative [4].

High impact information on LY6D

• The E48 antigen, a putative human homologue of the 20-kD protein present in desmosomal preparations of bovine muzzle, and formerly called desmoglein III (dg4), is a promising target antigen for antibody-based therapy of squamous cell carcinoma in man [5].
• Transfection of mouse SV40-polyoma transformed mouse NIH/3T3 cells with the E48 cDNA confirmed that the antigen is likely to be involved in cell-cell adhesion [5].
• A cDNA clone encoding the E48 antigen was isolated by expression cloning in COS cells [5].
• The gene encoding the E48 antigen is a single copy gene, located on human chromosome 8 in the 8q24-qter region [5].
• We have shown phenotypic modulation of tumor cell behavior by E48 expression, including enhanced cell migration in vitro and tumor cell dissemination in vivo [2].

Chemical compound and disease context of LY6D

• Clinical imaging of head and neck cancer with technetium-99m-labeled monoclonal antibody E48 IgG or F(ab')2 [6].
• One hundred and nineteen tissue samples from 47 bladder carcinomas were tested for reactivity with E48, using fresh frozen, sublimate formalin, and formalin fixed tissue [4].

Biological context of LY6D

• The functional significance of the E48-mediated up-regulation of Sialyl Lewis a was demonstrated in rolling experiments on E-selectin bearing surfaces under physiological conditions of shear flow and on tumor necrosis factor alpha-activated human umbilical venous endothelial cells [7].
• Biodistribution and pharmacokinetics of radiolabeled mAb E48 IgG and E48 F(ab')2 were analyzed and compared in 39 patients with histologically proven squamous cell carcinoma of the head and neck who were included in a radioimmunoscintigraphy study and underwent surgery 44 h after injection [8].
• These data suggest that a specific allosteric binding site on b5, which includes residues E48, E49, and possibly R52, mediates the stimulation of 17,20-lyase activity [9].
• From the tissue distribution of 800 microCi MAb E48, the absorbed cumulative radiation doses of tumour and various organs were calculated using the trapezoid integration method for the area under the curve [10].
• Moreover, it was shown that cmAb E48 is highly capable of lysing HNSCC targets in ADCC assays in vitro, whereas the mmAb appeared to be almost inactive [11].

Anatomical context of LY6D

• Moreover, expression of Ly-6K was shown in HNSCC cell lines, in which no E48 expression could be detected [12].
• The diagnostic value of 99mTc-labeled monoclonal antibody E48 F(ab')2 (750 MBq, 1 mg) was evaluated in 10 patients with a histologically proven squamous cell carcinoma of the head and neck and with clinical evidence of cervical lymph node involvement [13].
• Clinical significance of micrometastatic cells detected by E48 (Ly-6D) reverse transcription-polymerase chain reaction in bone marrow of head and neck cancer patients [14].
• Tumor uptake of 99mTc-labeled E48 IgG was high, ranging from 0.007 to 0.082% of the injected dose/g, with a mean of 0.031 +/- 0.020% of the injected dose/g. The mean tumor:nontumor ratio of this conjugate was 2.8 for mucosa, 4.6 for bone marrow aspirate, 4.1 for blood, 20.3 for fat, and 21.0 for muscle [8].
• In cells of normal oral mucosa, the E48 antigen was expressed on the plasmalemma, particularly associated with desmosomes, suggesting involvement of the E48 antigen in intercellular adhesion [15].

Associations of LY6D with chemical compounds

• Experimental groups received a single bolus injection of 200 [number of mice (n) = 6, number of tumors (t) = 11], 400 (n = 6, t = 11), 500 (n = 6, t = 12), or 600 (n = 5, t = 9) microCi 186Re-labeled MAb E48 IgG; control animals were given diluent (n = 4, t = 8) [16].
• In comparison, injection of 100 micrograms of a MAb E48 coupled to 2 micrograms of fluorescein gave a specific green fluorescence signal in the tumor xenografts, which was detectable, however, only after removing the mouse skin [17].
• The former cells also expressed higher levels of two major fucosylated glycans (the selectin ligand, Sialyl Lewis a, and VIM-2) than the E48 antisense transfectants [7].
• Three groups of patients were distinguished: group 1 (n = 19) received technetium-99m (99mTc)-labeled E48 F(ab')2, group 2 (n = 9) received 99mTc-labeled E48 IgG, and group 3 (n = 11) received 99mTc- and 131I-labeled E48 IgG as well as 125I-labeled F(ab')2 [8].
• The D48E variant possessed an additional residue of gamma-carboxyglutamic acid (Gla), showing that E48 was gamma-carboxylated [18].

Other interactions of LY6D

• 3. Genes encoding at least two other GPI-anchored molecules, E48 and RIG-E, are also located in this region [19].

Analytical, diagnostic and therapeutic context of LY6D

• A cytotoxin-armed antibody reactive with one of these drug-induced surface proteins, the LY6D/E48 antigen, originally identified as the target of a monoclonal antibody reactive with squamous cell carcinomas, caused complete regression of colorectal tumor xenografts in mice treated with CPT-11, whereas either agent alone was less effective [20].
• These preliminary data indicate that radioimmunoscintigraphy with monoclonal antibody E48 may be helpful in the diagnosis of metastatic and recurrent head and neck cancer [13].
• There were 2 false-positive observations with monoclonal antibody E48 and 3 with palpation [13].
• Moreover, the expression levels of Sialyl Lewis a was significantly up-regulated on HNSCC upon ligation of E48 by anti-E48 antibodies [7].
• Immunoblotting revealed that E 48 recognizes a 22 kd molecule [3].

References