Abstract The complementarity determining region, or idiotype, of the surface immunoglobulin receptor is a true tumor-specific marker on B-cell lymphomas unique to each patient. Antibodies against idiotype can induce complete regression of lymphoma in patients, but since this requires the generation of a custom monoclonal antibody for each patient, it has not been practical. We have developed a method for targeting idiotype using a novel construct that we refer to as a “semi-synthetic peptibody”. It consists of a synthetic peptide ligand for idiotype that is covalently linked to the amino terminus of a recombinant IgG Fc domain. Peptide ligands for idiotype can be identified by high throughput screens of random peptide libraries and produced inexpensively by solid-phase synthesis. Linkage of these idiotype ligands to the Fc domain enhances their pharmacokinetics and augments their anti-tumor effect by activating innate immune effectors. Since each patient-specific synthetic peptide can be chemically linked to a common IgG Fc domain, this modular design yields a custom therapeutic that may be more practical to produce than a unique biologic monoclonal antibody. We demonstrate that semi-synthetic peptibodies bind specifically to the idiotype of tumor cells and induce apoptosis by crosslinking surface immunoglobulin. Additionally, they trigger antibody dependent cellular cytotoxicity, antibody mediated phagocytosis, and complement-mediated lysis of opsonized lymphoma cells in vitro. They possess a favorable pharmacokinetic profile and are sufficient to clear tumor in SCID mice challenged intravenously with a luciferase-labeled human lymphoma cell line. Tumor clearance in vitro and in vivo mediated by peptibody was superior to that achievable with an anti-idiotype monoclonal antibody. Thus, semi-synthetic anti-idiotype peptibodies demonstrate multimodal activity against lymphoma cells in vitro and clear human lymphoma in a disseminated xenograft model. This modular, semi-synthetic design may enable a personalized and targeted therapy that is feasible to produce for patients with B-cell lymphoma. Citation Format: James Torchia, Patrick Ng, Homer Chen, Kipp Weiskopf, Ronald Levy. Semi-synthetic peptibodies are a novel personalized therapeutic with activity against lymphoma in vitro and in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 648. doi:10.1158/1538-7445.AM2014-648