title: Balancing Efficacy and Safety of an Anti-DLL4 Antibody through Pharmacokinetic Modulation.
abstract: OBJECTIVE
  Although agents targeting Delta-like ligand 4 (DLL4) have shown great promise for angiogenesis-based cancer therapy, findings in recent studies have raised serious safety concerns. To further evaluate the potential for therapeutic targeting of the DLL4 pathway, we pursued a novel strategy to reduce toxicities related to DLL4 inhibition by modulating the pharmacokinetic (PK) properties of an anti-DLL4 antibody.
  
  
  METHODS
  The F(ab')2 fragment of anti-DLL4 antibody (anti-DLL4 F(ab')2) was generated and assessed in efficacy and toxicity studies.
  
  
  RESULTS
  Anti-DLL4 F(ab')2 enables greater control over the extent and duration of DLL4 inhibition, such that intermittent dosing of anti-DLL4 F(ab')2 can maintain significant antitumor activity while markedly mitigating known toxicities associated with continuous pathway inhibition.
  
  
  CONCLUSIONS
  PK modulation has potentially broad implications for development of antibody-based therapeutics. Our safety studies with anti-DLL4 F(ab')2 also provide new evidence reinforcing the notion that the DLL4 pathway is extremely sensitive to pharmacologic perturbation, further underscoring the importance of exercising caution to safely harness this potent pathway in humans.
authors.affiliation: Development Sciences, Genentech, Inc., South San Francisco, California.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Couch
authors.affiliation: Molecular Oncology, Genentech, Inc., South San Francisco, California.
authors.forename: Gu
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Development Sciences, Genentech, Inc., South San Francisco, California.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Beyer
authors.affiliation: Development Sciences, Genentech, Inc., South San Francisco, California.
authors.forename: Christina L Zuch
authors.initials: CL
authors.lastname: de Zafra
authors.affiliation: Development Sciences, Genentech, Inc., South San Francisco, California.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Gupta
authors.affiliation: Development Sciences, Genentech, Inc., South San Francisco, California.
authors.forename: Amrita V
authors.initials: AV
authors.lastname: Kamath
authors.affiliation: Biostatistics, Genentech, Inc., South San Francisco, California.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Lewin-Koh
authors.affiliation: Development Sciences, Genentech, Inc., South San Francisco, California.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Tarrant
authors.affiliation: Development Sciences, Genentech, Inc., South San Francisco, California.
authors.forename: Krishna P
authors.initials: KP
authors.lastname: Allamneni
authors.affiliation: Development Sciences, Genentech, Inc., South San Francisco, California.
authors.forename: Gary
authors.initials: G
authors.lastname: Cain
authors.affiliation: In Vivo Pharmacology, Genentech, Inc., South San Francisco, California.
authors.forename: Sharon
authors.initials: S
authors.lastname: Yee
authors.affiliation: In Vivo Pharmacology, Genentech, Inc., South San Francisco, California.
authors.forename: Sarajane
authors.initials: S
authors.lastname: Ross
authors.affiliation: Biochemical and Cellular Pharmacology, South San Francisco, California.
authors.forename: Ryan
authors.initials: R
authors.lastname: Cook
authors.affiliation: Biochemical and Cellular Pharmacology, South San Francisco, California.
authors.forename: Siao Ping
authors.initials: SP
authors.lastname: Tsai
authors.affiliation: Development Sciences, Genentech, Inc., South San Francisco, California.
authors.forename: Jane
authors.initials: J
authors.lastname: Ruppel
authors.affiliation: Molecular Oncology, Genentech, Inc., South San Francisco, California.
authors.forename: John Brady
authors.initials: JB
authors.lastname: Ridgway
authors.affiliation: Protein Chemistry, Genentech, Inc., South San Francisco, California.
authors.forename: Maciej
authors.initials: M
authors.lastname: Paluch
authors.affiliation: Protein Chemistry, Genentech, Inc., South San Francisco, California.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Hass
authors.affiliation: Purification Development, Genentech, Inc., South San Francisco, California.
authors.forename: Jayme
authors.initials: J
authors.lastname: Franklin
authors.affiliation: Molecular Oncology, Genentech, Inc., South San Francisco, California. minhong@gene.com.
authors.forename: Minhong
authors.initials: M
authors.lastname: Yan
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008252:Macaca fascicularis; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D051381:Rats; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007140:Immunoglobulin Fab Fragments; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C064045:delta protein