With the increasing prevalence of cancers, new therapeutic approaches are constantly needed and immunotherapies have been rapidly introduced into clinical practice. Although immunotherapies are associated with higher efficacy when compared or combined to traditional chemotherapies, tumours often end up escaping treatment. Therefore, there are still considerable unmet medical needs to improve the efficacy of immunotherapeutic strategies, with the goal of moving towards chemotherapy-free regimens. In this regard, we have developed an innovative strategy of destructive tumour cell targeting using selective local complement activation. The technology is unique, allowing multivalent expression of two complement effectors (Factor H-Related Protein 4 and Fc) associated with a targeting function to selectively target HER2-tumour or CD20-lymphoma cells, based on a biological C4bp scaffold. Our novel immunoconjugates, called CoMiX (COmplement Multimer Immunotherapeutic compleXes), demonstrate in vitro higher efficacy in complement activation at the surface of tumour cells, cell direct cytotoxicity, NK cell activation and phagocytosis as compared to the reference therapeutic monoclonal antibodies. A Proof-of-Concept (PoC) development program is now needed to validate the in vivo therapeutic potency of CoMiX in two tumour models representative of solid tumours (HER2, known to be highly resistant to complement activation) and liquid tumours (CD20, more sensitive to complement activation), and to confirm their safety and stability. In the present PoC project, we will study in vivo the therapeutic efficacy of our lead CoMiX immunoconjugates in Her2 tumour and lymphoma xenograft models, and compare it to standard-of-care antibodies, alone or in combination. That proof of concept is essential to decide on all further developments for CoMiX as the strategies of development as biopharmaceuticals and/or as a technical platform to improve the therapeutic features of marketed antibodies are possible.