Engineering and therapeutic application of single-chain bivalent TGF-β family traps

Molecular Cancer Therapeutics
John C ZwaagstraMaureen D O'Connor-McCourt

Abstract

Deregulation of TGF-β superfamily signaling is a causative factor in many diseases. Here we describe a protein engineering strategy for the generation of single-chain bivalent receptor traps for TGF-β superfamily ligands. Traps were assembled using the intrinsically disordered regions flanking the structured binding domain of each receptor as "native linkers" between two binding domains. This yields traps that are approximately threefold smaller than antibodies and consists entirely of native receptor sequences. Two TGF-β type II receptor-based, single-chain traps were designed, termed (TβRII)2 and (TβRIIb)2, that have native linker lengths of 35 and 60 amino acids, respectively. Both single-chain traps exhibit a 100 to 1,000 fold higher in vitro ligand binding and neutralization activity compared with the monovalent ectodomain (TβRII-ED), and a similar or slightly better potency than pan-TGF-β-neutralizing antibody 1D11 or an Fc-fused receptor trap (TβRII-Fc). Despite its short in vivo half-life (<1 hour), which is primarily due to kidney clearance, daily injections of the (TβRII)2 trap reduced the growth of 4T1 tumors in BALB/c mice by 50%, an efficacy that is comparable with 1D11 (dosed thrice weekly). In addition, (TβRII)2 ...Continue Reading

References

Jan 1, 1990·Annals of the New York Academy of Sciences·M B Sporn, A B Roberts
Jul 6, 2000·Nature Structural Biology·T KirschM K Dreyer
Sep 22, 2001·Biomolecular Engineering·A A KorttP J Hudson
Jan 30, 2002·Experimental Biology and Medicine·Ye-Guang ChenShao-Yao Ying
Aug 15, 2002·Proceedings of the National Academy of Sciences of the United States of America·Jocelyn HolashJohn S Rudge
Dec 17, 2002·Nature Medicine·Aris N EconomidesNeil Stahl
Jun 11, 2003·Investigational New Drugs·Slawomir Wojtowicz-Praga
Mar 2, 2005·Nature Reviews. Molecular Cell Biology·H Jane Dyson, Peter E Wright
Dec 7, 2005·Proceedings of the National Academy of Sciences of the United States of America·Se-Jin LeeNeil M Wolfman
Dec 27, 2005·Current Opinion in Genetics & Development·Carlos L Arteaga
May 5, 2006·Proceedings of the National Academy of Sciences of the United States of America·George P AllendorphSenyon Choe
May 6, 2006·Arteriosclerosis, Thrombosis, and Vascular Biology·Alex Bobik
Aug 4, 2006·Reproduction : the Official Journal of the Society for the Study of Fertility·S Jack LinTeresa K Woodruff
Sep 26, 2006·Mutation Research·Chantal Rodgarkia-DaraMichael Grusch
Jan 24, 2007·Journal of Chemical Information and Modeling·Marwen NaïmEnrico O Purisima
Sep 21, 2007·BMC Cell Biology·Lior ZilberbergDaniel B Rifkin
Sep 28, 2007·Anti-cancer Agents in Medicinal Chemistry·Anna Alexeyevna MourskaiaPeter Michael Siegel
May 20, 2008·The FEBS Journal·Andrzej GalatAndré Ménez
May 24, 2008·Protein Engineering, Design & Selection : PEDS·Erik V VeronaLu-Zhe Sun
Oct 29, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Ryo UedaHideho Okada
Nov 6, 2009·Current Opinion in Biotechnology·Chichi Huang
Nov 21, 2009·Cytokine & Growth Factor Reviews·Joachim NickelThomas D Mueller
May 26, 2010·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·James R EdwardsGregory R Mundy
Apr 20, 2011·The International Journal of Biochemistry & Cell Biology·Vladimir N Uversky
Jul 2, 2011·Growth Factors·Lukas J A C Hawinkels, Peter Ten Dijke

❮ Previous
Next ❯

Citations

May 10, 2016·Analytical Biochemistry·Shima Moradi-KalbolandiMohammad Ali Shokrgozar
Sep 11, 2016·Protein Engineering, Design & Selection : PEDS·Kevin A HenryC Roger MacKenzie
Jul 28, 2020·Nature Reviews. Clinical Oncology·Rik DerynckRosemary J Akhurst
Apr 10, 2021·The Journal of Pathology·Erine H BudiRik Derynck
Jul 3, 2021·Cancers·Ester Gonzalez-SanchezIsabel Fabregat
Jun 7, 2021·Molecular Therapy : the Journal of the American Society of Gene Therapy·Bai LiuHing C Wong
Sep 17, 2021·Scientific Reports·Ravindra KumarRoselyne Castonguay
Nov 13, 2021·Frontiers in Bioengineering and Biotechnology·João Q CoentroDimitrios I Zeugolis

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.