Inhibition of pancreatic carcinoma by homo- and heterocombinations of antibodies against EGF-receptor and its kin HER2/ErbB-2

Significance Prognosis of pancreatic ductal adenocarcinoma (PDAC) remains very poor, with 5-y survival less than 10%. Unfortunately, adjuvant therapies are only weakly effective, and only one molecular targeted drug, a kinase inhibitor of epidermal growth factor receptor (EGFR), has been clinically approved. Hence, we examined antibodies to EGFR and to its sibling, HER2. While single antibodies to these receptors only weakly retarded growth of human PDAC in animals, significantly stronger inhibition was observed when we combined two antibodies to EGFR or two antibodies to HER2. Similarly, simultaneous inhibition of both EGFR and HER2, using a pair of antibodies, resulted in enhanced efficacy. These observations predict that targeting EGFR and HER2, by using pairs of monoclonal antibodies, might translate to better treatment of PDAC patients. Due to intrinsic aggressiveness and lack of effective therapies, prognosis of pancreatic cancer remains dismal. Because the only molecular targeted drug approved for pancreatic ductal adenocarcinoma is a kinase inhibitor specific to the epidermal growth factor receptor (EGFR), and this receptor collaborates with another kinase, called HER2 (human EGF-receptor 2), we assumed that agents targeting EGFR and/or HER2 would effectively retard pancreatic ductal adenocarcinoma. Accordingly, two immunological strategies were tested in animal models: (i) two antibodies able to engage distinct epitopes of either EGFR or HER2 were separately combined, and (ii) pairs of one antibody to EGFR and another to HER2. Unlike the respective single monoclonal antibodies, which induced weak effects, both types of antibody combinations synergized in animals in terms of tumor inhibition. Immunological cooperation may not depend on receptor density, antigenic sites, or the presence of a mutant RAS protein. Nevertheless, both types of antibody combinations enhanced receptor degradation. Future efforts will examine the feasibility of each strategy and the potential of combining them to achieve sustained tumor inhibition.

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