Targeting Anti-TGF-β Therapy to Fibrotic Kidneys with a Dual Specificity Antibody Approach.

Targeted delivery of a therapeutic agent to a site of pathology to ameliorate disease while limiting exposure at undesired tissues is an aspirational treatment scenario. Targeting diseased kidneys for pharmacologic treatment has had limited success. We designed an approach to target an extracellular matrix protein, the fibronectin extra domain A isoform (FnEDA), which is relatively restricted in distribution to sites of tissue injury. In a mouse unilateral ureteral obstruction (UUO) model of renal fibrosis, injury induced significant upregulation of FnEDA in the obstructed kidney. Using dual variable domain Ig (DVD-Ig) technology, we constructed a molecule with a moiety to target FnEDA and a second moiety to neutralize TGF-β After systemic injection of the bispecific TGF-β + FnEDA DVD-Ig or an FnEDA mAb, chemiluminescent detection and imaging with whole-body single-photon emission computed tomography (SPECT) revealed significantly higher levels of each molecule in the obstructed kidney than in the nonobstructed kidney, the ipsilateral kidney of sham animals, and other tissues. In comparison, a systemically administered TGF-β mAb accumulated at lower concentrations in the obstructed kidney and exhibited a more diffuse whole-body distribution. Systemic administration of the bispecific DVD-Ig or the TGF-β mAb (1-10 mg/kg) but not the FnEDA mAb attenuated the injury-induced collagen deposition detected by immunohistochemistry and elevation in Col1a1, FnEDA, and TIMP1 mRNA expression in the obstructed kidney. Overall, systemic delivery of a bispecific molecule targeting an extracellular matrix protein and delivering a TGF-β mAb resulted in a relatively focal uptake in the fibrotic kidney and reduced renal fibrosis.

[1]  R. Loebbert,et al.  Pharmacokinetics and Tolerability of a Dual Variable Domain Immunoglobulin ABT‐981 Against IL‐1α and IL‐1β in Healthy Subjects and Patients With Osteoarthritis of the Knee , 2016, Journal of clinical pharmacology.

[2]  S. Dooley,et al.  TGF‐β signalling and liver disease , 2016, The FEBS journal.

[3]  F. Bootz,et al.  Alternatively Spliced EDA Domain of Fibronectin Is a Target for Pharmacodelivery Applications in Inflammatory Bowel Disease , 2015, Inflammatory bowel diseases.

[4]  L. Chu,et al.  ‘Smart’ nanoparticles as drug delivery systems for applications in tumor therapy , 2015, Expert opinion on drug delivery.

[5]  Xiaoyuan Chen,et al.  Aptamer-Drug Conjugates. , 2015, Bioconjugate chemistry.

[6]  Vivek Dave,et al.  Colon-Targeted Oral Drug Delivery Systems: Design Trends and Approaches , 2015, AAPS PharmSciTech.

[7]  C. Pitzalis,et al.  Trojan horses and guided missiles: targeted therapies in the war on arthritis , 2015, Nature Reviews Rheumatology.

[8]  Mary E. Choi,et al.  Therapeutic targets for treating fibrotic kidney diseases. , 2015, Translational research : the journal of laboratory and clinical medicine.

[9]  Jun Li,et al.  TGF-β/Smad signaling in renal fibrosis , 2015, Front. Physiol..

[10]  C. Sheridan Amgen's bispecific antibody puffs across finish line , 2015, Nature Biotechnology.

[11]  J. Berzofsky,et al.  Cutaneous keratoacanthomas/squamous cell carcinomas associated with neutralization of transforming growth factor β by the monoclonal antibody fresolimumab (GC1008) , 2015, Cancer Immunology, Immunotherapy.

[12]  Mark E. Davis,et al.  Targeting therapeutics to the glomerulus with nanoparticles. , 2013, Advances in chronic kidney disease.

[13]  C. Jakob,et al.  Structure reveals function of the dual variable domain immunoglobulin (DVD-Ig™) molecule , 2013, mAbs.

[14]  R. Akhurst,et al.  Complexities of TGF-β Targeted Cancer Therapy , 2012, International journal of biological sciences.

[15]  E. White,et al.  Fibronectin splice variants: Understanding their multiple roles in health and disease using engineered mouse models , 2011, IUBMB life.

[16]  G. Remuzzi,et al.  A phase 1, single-dose study of fresolimumab, an anti-TGF-β antibody, in treatment-resistant primary focal segmental glomerulosclerosis , 2011, Kidney international.

[17]  K. Sharma,et al.  Targeted renal therapies through microbubbles and ultrasound. , 2010, Advanced drug delivery reviews.

[18]  W. Hennink,et al.  Drug targeting to the kidney: Advances in the active targeting of therapeutics to proximal tubular cells. , 2010, Advanced drug delivery reviews.

[19]  R. Goldschmeding,et al.  Targeting podocyte-associated diseases. , 2010, Advanced drug delivery reviews.

[20]  H. Bagavant,et al.  Mesangial pathology in glomerular disease: targets for therapeutic intervention. , 2010, Advanced drug delivery reviews.

[21]  G. Wolf,et al.  TGF-beta and fibrosis in different organs - molecular pathway imprints. , 2009, Biochimica et biophysica acta.

[22]  E. White,et al.  New insights into form and function of fibronectin splice variants , 2008, The Journal of pathology.

[23]  S. Twigg,et al.  Fibrosis in diabetes complications: Pathogenic mechanisms and circulating and urinary markers , 2008, Vascular health and risk management.

[24]  T. Wynn,et al.  Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. , 2007, The Journal of clinical investigation.

[25]  H. Baelde,et al.  Alternatively spliced isoforms of fibronectin in immune‐mediated glomerulosclerosis: the role of TGFβ and IL‐4 , 2004, The Journal of pathology.

[26]  E. Bottinger,et al.  TGF-β signaling in renal disease , 2002 .

[27]  H. Baelde,et al.  Distribution of fibronectin isoforms in human renal disease , 2001, The Journal of pathology.

[28]  B. S. Lee,et al.  Human leiomyoma smooth muscle cells show increased expression of transforming growth factor-beta 3 (TGF beta 3) and altered responses to the antiproliferative effects of TGF beta. , 2001, The Journal of clinical endocrinology and metabolism.

[29]  D. Poppas,et al.  Antibody to transforming growth factor-beta ameliorates tubular apoptosis in unilateral ureteral obstruction. , 2000, Kidney international.

[30]  T. McCaffrey,et al.  Transforming growth factor-β receptor types I and II are expressed in renal tubules and are increased after chronic unilateral ureteral obstruction , 1998 .

[31]  M. Delp,et al.  Physiological Parameter Values for Physiologically Based Pharmacokinetic Models , 1997, Toxicology and industrial health.

[32]  Jia Guo,et al.  Neutralization of TGF-β by Anti-TGF-β Antibody Attenuates Kidney Hypertrophy and the Enhanced Extracellular Matrix Gene Expression in STZ-Induced Diabetic Mice , 1996, Diabetes.

[33]  T. McCaffrey,et al.  Chronic unilateral ureteral obstruction is associated with interstitial fibrosis and tubular expression of transforming growth factor-beta. , 1996, Laboratory investigation; a journal of technical methods and pathology.

[34]  C. Nast,et al.  Expression of transforming growth factor-β isoforms in human glomerular diseases , 1996 .

[35]  M. O’Connor-McCourt,et al.  Characterization of recombinant soluble human transforming growth factor-β receptor Type II (rhTGF-βsRII) , 1995 .

[36]  W. Border,et al.  Transforming Growth Factor β in Tissue Fibrosis , 1994 .

[37]  A. Michael,et al.  Interstitial fibrosis in obstructive nephropathy. , 1993, Kidney international.

[38]  S. Klahr,et al.  Increased expression of TGF-beta 1 mRNA in the obstructed kidney of rats with unilateral ureteral ligation. , 1993, Kidney international.

[39]  G. Proetzel,et al.  Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease , 1992, Nature.

[40]  J. Dasch,et al.  Monoclonal antibodies recognizing transforming growth factor-beta. Bioactivity neutralization and transforming growth factor beta 2 affinity purification. , 1989, Journal of immunology.

[41]  M. Gacka,et al.  [The role of transforming growth factor-beta in the pathogenesis of diabetic retinopathy]. , 2006, Przeglad lekarski.