Targeting lymphoma with modular anti-idiotype peptibodies

Stanford University, Stanford CA

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Abstract

Current therapies for non-hodgkin lymphoma (NHL) are initially effective for most patients but result in diminished efficacy and cumulative toxicity with repeated use and the majority of patients relapse and succumb to progressive disease (1). A more targeted therapy that utilizes a novel mechanism of action would be a welcome addition to the arsenal of therapies available for management of this disease. The majority of NHL tumors arise from a clonal population of B-cells. The complementarity determining region (CDR) of the surface immunoglobulin receptor, also known as idiotype, is nearly identical on all malignant cells in B-cell lymphomas and is distinct from the idiotype present on non-malignant B-cells. Thus, idiotype is a true tumor-specific surface marker and an attractive candidate for targeted cancer therapy. Antibodies against idiotype have been shown to induce complete regression of lymphoma in patients (3). But since the idiotype on each patient's cancer is unique, this therapeutic approach requires the generation of a custom monoclonal antibody for each patient - a requirement that raises technical and practical barriers that prohibit the widespread translation of this approach. We are developing a method of targeting idiotype that may be more practical to scale. Short peptides with targeted affinity for idiotype can be identified by high throughput screens, produced rapidly and inexpensively by automated solid-phase synthesis, and can directly induce apoptosis of lymphoma cells in-vitro (4, 5). Although these peptides appear to be poor drugs in animal models, affixing them to the amino terminus of an IgG Fc domain might improve their potency by extending their pharmacokinetic half-life and by augmenting their anti-tumor effect through activation of innate immune effector mechanisms. Since the patient-specific portion would be a short synthetic peptide and the biologic Fc domain would be produced in bulk for all patients, this approach may be more practical than producing a unique biologic monoclonal antibody for each patient. We hypothesize that this semi-synthetic construct, that we term a modular peptibody, will be sufficient for lymphoma tumor clearance of a human lymphoma xenograft in a murine model system.