Methods and systems for predicting misfolded protein epitopes
a protein epitope and protein technology, applied in the field of methods, can solve the problems of uncontrolled proliferation, low sequence similarity, and low prediction accuracy, and achieve the effect of high sequence similarity and high probability of unfolding
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example 1
hSOD1
[0308]As described in WO2007 / 098607, Cashman et al teach the production of an hSOD1 antibody that was raised against the 35-45 region of hSOD1, a region essentially predicted by the present epitope prediction methods as constituting an hSOD1 epitope with a propensity for unfolding. The predicted sequence of 35-41 is essentially a truncated version of the 35-45 region targeted by the published antibody. The antibody production and testing work published in that patent application is reproduced below.
[0309]For antibody production, 4 female BALB / c mice were initially immunized by intraperitoneal injections with 25 μg of immunogen comprising peptide C-IKGLTEGLHGF (SEQ ID NO:89, corresponding to hSOD1 residues 35-45) coupled to KLH by disulfide formation with a cysteine that was added to the N terminus, in Complete Freund's Adjuvant. Four subsequent boosts were administered as above, spaced at 3 week intervals, with Incomplete Freund's Adjuvant. When the serum titre had risen more t...
example 2
EGFR
[0312]As noted in Table 1 herein, application of the epitope prediction methods to the structure of human epidermal growth factor receptor (hEGFR) indicates that an epitope with propensity for unfolding resides at residues 288-301, having the peptide sequence GADSYEMEEDGVRK (SEQ ID No. 76). The EGFR itself is a protein targeted for therapeutic intervention by a variety of antibodies that are either marketed (cetuximab as Erbitux®, panitumumab as Vectibix®) or in clinical development (nimotuzumab). These antibodies have efficacy in the treatment of various solid tumours, including head and neck as well as pediatric glioma. With the exception of nimotuzumab, the antibodies targeting EGFR raise significant toxicities associated particularly with their interaction with keratinocytes—while improvements can be shown in the stasis or regression of tumour growth, recipients show a variety of skin disorders including severe rash. This results from the antibody's non-selective binding not...
example 3
Additional EGFR Epitopes
[0314]Rabbits were immunized with EGFR peptides predicted by the epitope prediction methods to have a propensity for unfolding to present unique epitopes (see Table 1). For convenience, rabbit E1 was immunized with 8 peptides, i.e., peptides having SEQ ID Nos. 67, 69, 70, 72, 73, 75, and 78. Rabbit E2 was immunized with 7 peptides, i.e., peptides having SEQ ID Nos. 66, 71, 74, 76, 77, 79 and 80.
[0315]Antisera from these rabbits were tested for their ability to bind to one normal cell (HUVEC) and 14 tumor cells. Preimmune rabbit serum was used as a binding control. Each cell was also evaluated for its level of EGFR expression using a commercially available anti-EGFR antibody compared to an isotype control antibody.
[0316]On analysis of the results, it was observed that the normal cells (HUVEC) express low levels of EGFR and do not bind antisera from rabbit E1 or E2. Two of the tumors tested (human GI stromal colon tumour LTL-257, and human cervical carcinoma ce...
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