Abstract
The human epidermal growth factor receptor (HER1) and its partner HER2 are extensively described oncogenes and validated targets for cancer therapy. However, the effectiveness of monospecific therapies targeting these receptors is hampered by resistance emergence, which is frequently associated with the upregulation of other members of HER family. Combined therapies using monoclonal antibodies or tyrosine kinase inhibitors have been suggested as a promising strategy to circumvent this resistance mechanism. We propose an alternative approach based on simultaneous inactivation of HER1 and HER2 by multi-epitope blockade with specific polyclonal antibodies induced by vaccination. Elicited antibodies impaired both receptors activation and induced their degradation, which caused the inhibition of down-signaling cascades. This effect was translated into cell cycle arrest and apoptosis induction of human tumor cells. Elicited antibodies were able to reduce the viability of a panel of human tumor lines with differential expression levels of HER1 and HER2. The most significant effects were obtained in the tumor lines with lower expression levels of both receptors. These new insights would contribute to the rational design of HER receptors targeting multivalent vaccines, as an encouraging approach for the treatment of cancer patients.
Highlights
The human epidermal growth factor receptor (EGFR or HER1) family comprises four receptors (HER1-4) with tyrosine kinase activity [1]
The specificity of the response was not related with the adjuvant, since antiHER1/HER2 antibodies were not induced in mice immunized only with VSSP (Supplementary Figure 1B)
polyclonal antibodies (PAbs) obtained with 400μg of both extracellular domains (ECD), prevented ligand-dependent activation of HER1 more effectively than the antibodies induced with 100μg of the antigens
Summary
The human epidermal growth factor receptor (EGFR or HER1) family comprises four receptors (HER1-4) with tyrosine kinase activity [1]. Some reports have described the association between HER1 and HER2 expression and activation with a decreased expression of MHC-I [4, 5] It has been described the linkage between HER1 activation and the increased expression of immune-suppressive molecules like PD-L1 [6], as well as the secretion of inflammatory cytokines in tumor cells [7, 8]. Despite recognized results achieved in clinic with cetuximab and trastuzumab (Herceptin), the most advanced MAbs targeting HER1 and HER2, respectively, only some patients are benefited The efficacy of these MAbs has been associated with high levels of expression, and absence of mutations in the targeted receptor [12, 13]. Blocking several epitopes in more than one HER family member could be a striking strategy to avoid resistance associated with the expression of these compensatory molecules
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