Abstract
Two HER2-specific mAbs, trastuzumab and pertuzumab (T+P), combined with chemotherapy comprise standard-of-care treatment for advanced HER2+ breast cancers (BC). While this antibody combination is highly effective, its synergistic mechanism-of-action (MOA) remains incompletely understood. Past studies have suggested that the synergy underlying this combination occurs through the different mechanisms elicited by these antibodies, with pertuzumab suppressing HER2 heterodimerization and trastuzumab inducing antitumor immunity. However, in vivo evidence for this synergy is lacking. In this study, we found that the therapeutic efficacy elicited by their combination occurs through their joint ability to activate the classical complement pathway, resulting in both complement-dependent cytotoxicity and complement-dependent cellular phagocytosis of HER2+ tumors. We also demonstrate that tumor C1q expression is positively associated with survival outcome in HER2+ BC patients and that complement regulators CD55 and CD59 were inversely correlated with outcome, suggesting the clinical importance of complement activity. Accordingly, inhibition of C1q in mice abolished the synergistic therapeutic activity of T+P therapy, whereas knockdown of CD55 and CD59 expression enhanced T+P efficacy. In summary, our study identifies classical complement activation as a significant antitumor MOA for T+P therapy that may be functionally enhanced to potentially augment clinical therapeutic efficacy.
Highlights
20% of breast cancers (BC) have amplified expression of HER2, an oncogenic ErbB family member transmembrane protein recognized as a driver for an aggressive cancer phenotype [1, 2]
We found that the addition of pertuzumab to trastuzumab therapy synergistically elicits activation of the classical complement pathway in vivo and is critical for the enhanced antitumor efficacy of this combination therapy
As multiple reports have indicated that pertuzumab inhibits tumor growth through blockade of HER2/HER3 dimerization and downstream oncogenic signaling, we speculated that synergy would be observed against HER2/HER3 expressing lines both in vitro and in vivo, while this synergy would not be observed in HER2+HER3– lines [16, 17]
Summary
20% of breast cancers (BC) have amplified expression of HER2, an oncogenic ErbB family member transmembrane protein recognized as a driver for an aggressive cancer phenotype [1, 2] Clinical outcomes for this disease have improved substantially with the advent and use of targeted HER2 mAb therapies, beginning with trastuzumab (Herceptin), which was approved in 1998 [3]. Trastuzumab treatment in combination with chemotherapy had positive outcomes, disease progression and recurrence continued to occur, especially in more advanced metastatic BC [4]. This led to the 2012 approval of another humanized antibody targeting HER2, pertuzumab (Perjeta), used in conjunction with trastuzumab [5]. Studies demonstrated that pertuzumab binds to the center of domain II of HER2, allowing for steric inhibition of HER2 heterodimerization with HER3/EGFR [12, 13], which impairs
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