Anton Simeonov Ph.D. National Institute of Health

Treatment of B-Cell Lymphomas with Monoclonal Antibodies Has Met With Low Success

Treatment of B-cell lymphomas with monoclonal antibodies, though promising in principle, has met with low success due to development of resistance over time. The tumor's resistance to the antibody is traced to the fact that individual tumors present unique and changing sets of epitopes associated with the malignancies in B-cell lymphomas, making anti-idiotypic therapy with traditional immunoglobulin G (IgG)-type antibodies highly impractical and ultimately unsuccessful, as such a traditional therapy would require a custom generation of anti-idiotype antibodies one patient at a time. Here, the team has provided a method of targeting lymphoma idiotype on a patient-specific basis by using semisynthetic anti-idiotype peptibodies (Figure 1). First, a recombinant murine IgG2a Fc domain was modified to carry an aminoterminal cysteine, which in turn served as a handle for a native chemical ligation later used to attach idiotype-binding peptides site selectively. The idiotype-binding peptides could in turn be easily identified through high-throughput screens of patient tumor cells against peptide libraries. In this manner, the peptibody combining an immunoglobulin Fc domain and malignant B-cell-specific peptide binder represents a therapeutic modality that is easier to scale up and personalize than a traditional monoclonal. Further, given that a single peptibody molecule can incorporate more than two antigen-binding domains, a higher avidity and cell-killing efficacy can be engineered. Finally, the peptibodies developed here were shown to kill tumor cells in vitro and to clear human lymphoma in a mouse xenograft model, thus offering a proof-of-principle for this novel therapeutic modality.


Figure 1. Concept overview. (A) Tumor idiotype is the variable region of the BCR on the surface of lymphoma cells. It is unique to the tumor clone and distinct from the idiotype on other B-cell clones. Peptibodies cross-link idiotype, triggering BCR signaling, resulting in activation-induced cell death, and opsonize tumor cells with an IgG Fc domain, promoting tumor clearance mediated by innate immune effector cells. (B) Schematic of semisynthetic anti-idiotype peptibody production. A random peptide library is screened to identify peptide sequences with idiotype-specific binding, which are synthesized and affixed to the amino terminus of a premade recombinant IgG Fc domain.


* Abstract from Proc Natl Acad Sci U S A 2016, in press. DOI: 10/1073/pnas.1603335113

B-cell lymphomas express a functionally active and truly tumor-specific cell-surface product, the variable region of the B-cell receptor (BCR), otherwise known as idiotype. The tumor idiotype differs, however, from patient to patient, making it a technical challenge to exploit for therapy. We have developed a method of targeting idiotype by using a semisynthetic personalized therapeutic that is more practical to produce on a patient-by-patient basis than monoclonal antibodies. In this method, a small peptide with affinity for a tumor idiotype is identified by screening a library, chemically synthesized, and then affixed to the amino terminus of a premade IgG Fc protein. We demonstrate that the resultant semisynthetic anti-idiotype peptibodies kill tumor cells in vitro with specificity, trigger tumor cell phagocytosis by macrophages, and efficiently clear human lymphoma in a murine xenograft model. This method could be used to target tumor with true precision on a personalized basis.








































Anton Simeonov, Ph.D., works at the NIH.

ASSAY & Drug Development Technologies, published by Mary Ann Liebert, Inc., offers a unique combination of original research and reports on the techniques and tools being used in cutting-edge drug development. The journal includes a "Literature Search and Review" column that identifies published papers of note and discusses their importance. GEN presents here one article that was analyzed in the "Literature Search and Review" column, published in Proceedings of the National Academy of Sciences titled "Targeting lymphoma with precision using semisynthetic anti-idiotype peptibodies", authors are Torchia J, Weiskopf K, Levy R.


 

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