title: Maximizing tumour exposure to anti-neuropilin-1 antibody requires saturation of non-tumour tissue antigenic sinks in mice.
abstract: OBJECTIVE
  Neuropilin-1 (NRP1) is a VEGF receptor that is widely expressed in normal tissues and is involved in tumour angiogenesis. MNRP1685A is a rodent and primate cross-binding human monoclonal antibody against NRP1 that exhibits inhibition of tumour growth in NPR1-expressing preclinical models. However, widespread NRP1 expression in normal tissues may affect MNRP1685A tumour uptake. The objective of this study was to assess MNRP1685A biodistribution in tumour-bearing mice to understand the relationships between dose, non-tumour tissue uptake and tumour uptake.
  
  
  METHODS
  Non-tumour-bearing mice were given unlabelled MNRP1685A at 10 mg·kg(-1) . Tumour-bearing mice were given (111) In-labelled MNRP1685A along with increasing amounts of unlabelled antibody. Blood and tissues were collected from all animals to determine drug concentration (unlabelled) or radioactivity level (radiolabelled). Some animals were imaged using single photon emission computed tomography - X-ray computed tomography.
  
  
  RESULTS
  MNRP1685A displayed faster serum clearance than pertuzumab, indicating that target binding affected MNRP1685A clearance. I.v. administration of (111) In-labelled MNRP1685A to tumour-bearing mice yielded minimal radioactivity in the plasma and tumour, but high levels in the lungs and liver. Co-administration of unlabelled MNRP1685A with the radiolabelled antibody was able to competitively block lungs and liver radioactivity uptake in a dose-dependent manner while augmenting plasma and tumour radioactivity levels.
  
  
  CONCLUSIONS
  These results indicate that saturation of non-tumour tissue uptake is required in order to achieve tumour uptake and acceptable exposure to antibody. Utilization of a rodent and primate cross-binding antibody allows for translation of these results to clinical settings.
authors.affiliation: Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech Research and Early Development, South San Francisco, CA, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bumbaca
authors.forename: Hong
authors.initials: H
authors.lastname: Xiang
authors.forename: C Andrew
authors.initials: CA
authors.lastname: Boswell
authors.forename: Ruediger E
authors.initials: RE
authors.lastname: Port
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Stainton
authors.forename: Eduardo E
authors.initials: EE
authors.lastname: Mundo
authors.forename: Sheila
authors.initials: S
authors.lastname: Ulufatu
authors.forename: Anil
authors.initials: A
authors.lastname: Bagri
authors.forename: Frank-Peter
authors.initials: FP
authors.lastname: Theil
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fielder
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Khawli
authors.forename: Ben-Quan
authors.initials: BQ
authors.lastname: Shen
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007205:Indium Radioisotopes / Q000737:chemistry; D007457:Iodine Radioisotopes / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D064847:Multimodal Imaging / Q000379:methods; D009374:Neoplasms, Experimental; D039942:Neuropilin-1 / Q000276:immunology*; D049268:Positron-Emission Tomography; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D039942:Neuropilin-1; C574067:vesencumab; C485206:pertuzumab
references.citation: Annu Rev Biomed Eng. 1999;1:241-63
references.pmid: 11701489
references.citation: MAbs. 2011 Jul-Aug;3(4):376-86
references.pmid: 21540647
references.citation: Br J Cancer. 2001 May 18;84(10):1424-31
references.pmid: 11355958
references.citation: J Mol Biol. 2007 Feb 23;366(3):815-29
references.pmid: 17196977
references.citation: Cancer Res. 2007 Jan 1;67(1):254-61
references.pmid: 17210705
references.citation: Eur J Cancer. 2004 Apr;40(6):837-44
references.pmid: 15120039
references.citation: N Engl J Med. 1993 Aug 12;329(7):459-65
references.pmid: 7687326
references.citation: Cancer Res. 1989 Oct 15;49(20):5656-63
references.pmid: 2790783
references.citation: Nat Rev Drug Discov. 2004 May;3(5):391-400
references.pmid: 15136787
references.citation: AAPS J. 2010 Mar;12(1):33-43
references.pmid: 19924542
references.citation: Cancer Res. 2006 Aug 1;66(15):7630-8
references.pmid: 16885363
references.citation: Nat Rev Cancer. 2006 Aug;6(8):583-92
references.pmid: 16862189
references.citation: Cancer Immunol Immunother. 2006 Jun;55(6):717-27
references.pmid: 16151804
references.citation: Clin Cancer Res. 2010 Feb 15;16(4):1085-7
references.pmid: 20145182
references.citation: Semin Oncol. 1999 Aug;26(4 Suppl 12):60-70
references.pmid: 10482195
references.citation: Cancer Cell. 2007 Jan;11(1):53-67
references.pmid: 17222790
references.citation: Expert Opin Biol Ther. 2001 Jul;1(4):719-32
references.pmid: 11727507
references.citation: J Nucl Med. 1990 Jul;31(7):1191-8
references.pmid: 2362198
references.citation: J Immunol. 1991 Sep 1;147(5):1548-56
references.pmid: 1715362
references.citation: J Biol Chem. 2002 Jul 5;277(27):24818-25
references.pmid: 11986311
references.citation: Nat Biotechnol. 2005 Sep;23(9):1147-57
references.pmid: 16151408
references.citation: Clin Cancer Res. 2003 Sep 1;9(10 Pt 1):3731-41
references.pmid: 14506165
references.citation: N Engl J Med. 1993 Oct 21;329(17):1219-24
references.pmid: 7692295
references.citation: Clin Cancer Res. 2010 Feb 15;16(4):1289-97
references.pmid: 20145187
references.citation: Trends Pharmacol Sci. 2008 Feb;29(2):57-61
references.pmid: 18179828
references.citation: Cancer Res. 1995 Oct 15;55(20):4611-22
references.pmid: 7553638
references.citation: Cancer Biol Ther. 2003 Jul-Aug;2(4 Suppl 1):S134-9
references.pmid: 14508091
references.citation: Exp Cell Res. 2006 Mar 10;312(5):584-93
references.pmid: 16445911
references.citation: Cancer Res. 1992 Nov 1;52(21):5940-7
references.pmid: 1394220
references.citation: Cancer Res. 2001 Jun 15;61(12):4750-5
references.pmid: 11406547
references.citation: J Clin Oncol. 2008 Jul 20;26(21):3650-2; author reply 3652-3
references.pmid: 18640947
references.citation: Br J Haematol. 2008 Feb;140(3):303-12
references.pmid: 18045353
references.citation: Clin Cancer Res. 2009 Mar 15;15(6):1860-4
references.pmid: 19240167
references.citation: Cancer Chemother Pharmacol. 2005 Nov;56(5):455-64
references.pmid: 15947929
references.citation: Mol Pharm. 2010 Oct 4;7(5):1848-57
references.pmid: 20704296
references.citation: Clin Cancer Res. 2004 Jul 15;10(14):4607-13
references.pmid: 15269131
references.citation: Cell. 1998 Mar 20;92(6):735-45
references.pmid: 9529250
references.citation: J Pharm Sci. 2004 Nov;93(11):2645-68
references.pmid: 15389672