Generation of antibody-based therapeutics targeting the Idiotype of B-cell Malignancies

Antibody Therapeutics
Emily WeissDavid FitzGerald

Abstract

A feature of many B-cell tumors is a surface-expressed immunoglobulin (sIg). The complementarity determiningregions (CDRs)of the sIg, termed the 'idiotype', are unique to each tumor. We report on a phage selection strategy to generate anti-idiotype therapeutics that react with sIg CDR3 sequences: the MEC1 B-cell tumor line was used as proof of concept. To create a mimetic of the MEC1 idiotype, CDR3 sequences from heavy and light chains of the sIg were grafted into a scFv framework scaffold. Using the Tomlinson I phage library of human scFvs, we enriched for binders to MEC1 CDR3 sequences over unrelated CDR3 sequences. By ELISA we identified 10 binder phage. Of these, five were sequenced, found to be unique and characterized further. By flow cytometry each of the five phage bound to MEC1 cells, albeit with different patterns of reactivity. To establish specificity of binding and utility, the scFv sequences from two of these binders (phage 1, and 7) were converted into antibody-toxin fusion proteins (immunotoxins) and also cloned into a human IgG1 expression vector. Binder-1 and -7 immunotoxins exhibited specific killing of MEC1 cells with little toxicity for non-target B-cell lines. The full-length antibody recreated from the bi...Continue Reading

References

May 15, 1992·Proceedings of the National Academy of Sciences of the United States of America·P CarterH M Shepard
Mar 4, 1982·The New England Journal of Medicine·R A MillerR Levy
Oct 28, 2008·Blood Reviews·Roch Houot, Ronald Levy
Jun 3, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Stephen J SchusterLarry W Kwak
Oct 15, 2011·Cancer Research·David J FitzGeraldIra Pastan
Mar 23, 2012·Nature Reviews. Cancer·Andrew M ScottLloyd J Old
Aug 22, 2012·Methods in Molecular Biology·Masanori Onda
Dec 26, 2012·Frontiers in Oncology·Thomas Kieber-EmmonsHeinz Kohler
Sep 26, 2013·Seminars in Cancer Biology·Carsten U Niemann, Adrian Wiestner
Apr 11, 2014·Immunologic Research·Michael S Khodadoust, Ash A Alizadeh
May 7, 2014·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Ronald LevyDan W Denney
Jul 26, 2014·Journal of Translational Medicine·Pier Adelchi RuffiniBjarne Bogen
Dec 3, 2014·Seminars in Oncology·Ulrich H WeidleUlrich Brinkmann
Dec 3, 2014·Seminars in Oncology·Sumita TrivediRobert L Ferris

❮ Previous
Next ❯

Citations


❮ Previous
Next ❯

Related Concepts

Related Feeds

Bacteriophage: Phage Therapy

Phage therapy uses bacterial viruses (bacteriophages) to treat bacterial infections and is widely being recognized as an alternative to antibiotics. Here is the latest research.

B-Cell Leukemia (Keystone)

B-cell leukemia includes various types of lymphoid leukemia that affect B cells. Here is the latest research on B-cell leukemia.

Related Papers

Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology
Xianliang HouHongyan Diao
Chromosome Research : an International Journal on the Molecular, Supramolecular and Evolutionary Aspects of Chromosome Biology
Jesús A Carballo, Rita S Cha
The Journal of Biological Chemistry
Paulina H WanrooijPeter M Burgers
© 2022 Meta ULC. All rights reserved