PMID- 22225620
OWN - NLM
STAT- MEDLINE
DCOM- 20121217
LR  - 20231104
IS  - 1478-6362 (Electronic)
IS  - 1478-6354 (Print)
IS  - 1478-6354 (Linking)
VI  - 14
IP  - 1
DP  - 2012 Jan 8
TI  - Safety, pharmacokinetics, and biologic activity of pateclizumab, a novel 
      monoclonal antibody targeting lymphotoxin alpha: results of a phase I randomized, 
      placebo-controlled trial.
PG  - R6
LID - 10.1186/ar3554 [doi]
AB  - INTRODUCTION: Pateclizumab (MLTA3698A) is a humanized mAb against lymphotoxin alpha 
      (LTalpha), a transiently expressed cytokine on activated B and T cells (Th1, Th17), 
      which are implicated in rheumatoid arthritis (RA) pathogenesis. This study was 
      conducted to assess the safety, tolerability, < NOTE: For clarity and per AMA/S-W 
      Style, please restore the use of Oxford/serial commas (ie: David likes vanilla, 
      strawberry, and chocolate ice cream) throughout. and biologic activity of single 
      and multiple doses of intravenous (IV) or subcutaneous (SC) pateclizumab in RA 
      patients. METHODS: The single ascending dose (SAD) phase in patients with stable 
      RA consisted of six cohorts (4:1 active:placebo at 0.3 mg/kg IV, 1.0 mg/kg IV, 
      1.0 mg/kg SC, 3.0 mg/kg IV, 3.0 mg/kg SC, and 5.0 mg/kg IV; n = 5/cohort). In the 
      multiple ascending dose (MAD) phase, patients with prespecified RA disease 
      activity received three doses of pateclizumab or placebo (4:1) every 2 weeks (1.0 
      mg/kg SC, n = 10; 3.0 mg/kg SC, n = 20; or 5.0 mg/kg IV, n = 5). Safety and 
      tolerability were assessed throughout, and clinical activity was determined after 
      three doses (Week 6). RESULTS: We observed no serious adverse events (AEs) or 
      dose-limiting toxicities, and the majority of AEs were mild to moderate. The 
      pharmacokinetic profiles were linear, and clearance was independent of dose. 
      Reductions in levels of serum CXCL13 were observed, supporting the biologic 
      activity of pateclizumab on the LTalpha pathway. Patients receiving pateclizumab in 
      the 3.0 mg/kg MAD group (3.0 mg/kg SC) demonstrated ACR20, ACR50, and ACR70 
      response rates at week 6 of 75%, 56% and 25%, respectively, compared with 57%, 
      29%, and 0% in the placebo group. The median Disease Activity Score in 28 joints, 
      C-reactive protein, reduction was 28% for pateclizumab, versus 8.4% for placebo. 
      CONCLUSIONS: Pateclizumabwas generally well-tolerated in RA patients. Preliminary 
      evidence of clinical activity was observed in active RA patients at the dose 
      level targeted for clinical effect.
FAU - Emu, Brinda
AU  - Emu B
AD  - Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
FAU - Luca, Diana
AU  - Luca D
FAU - Offutt, Carolyn
AU  - Offutt C
FAU - Grogan, Jane L
AU  - Grogan JL
FAU - Rojkovich, Bernadette
AU  - Rojkovich B
FAU - Williams, Marna B
AU  - Williams MB
FAU - Tang, Meina T
AU  - Tang MT
FAU - Xiao, Jim
AU  - Xiao J
FAU - Lee, June H
AU  - Lee JH
FAU - Davis, John C
AU  - Davis JC
LA  - eng
SI  - ClinicalTrials.gov/NCT00888745
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20120108
PL  - England
TA  - Arthritis Res Ther
JT  - Arthritis research & therapy
JID - 101154438
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antirheumatic Agents)
RN  - 0 (Chemokine CXCL13)
RN  - 0 (Lymphotoxin-alpha)
RN  - QOK1YYH7J2 (pateclizumab)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antibodies, Monoclonal, Humanized/adverse effects/*pharmacokinetics/*therapeutic 
      use
MH  - Antirheumatic Agents/adverse effects/pharmacokinetics/therapeutic use
MH  - Area Under Curve
MH  - Arthritis, Rheumatoid/blood/*drug therapy/immunology
MH  - Chemokine CXCL13/blood
MH  - Diarrhea/chemically induced
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Female
MH  - Headache/chemically induced
MH  - Humans
MH  - Injections, Intravenous
MH  - Injections, Subcutaneous
MH  - Lymphotoxin-alpha/*antagonists & inhibitors/immunology/metabolism
MH  - Male
MH  - Metabolic Clearance Rate
MH  - Middle Aged
MH  - Signal Transduction/drug effects/immunology
MH  - Treatment Outcome
MH  - *Young Adult
PMC - PMC3392792
EDAT- 2012/01/10 06:00
MHDA- 2012/12/18 06:00
PMCR- 2012/01/08
CRDT- 2012/01/10 06:00
PHST- 2011/08/19 00:00 [received]
PHST- 2011/11/07 00:00 [revised]
PHST- 2012/01/08 00:00 [accepted]
PHST- 2012/01/10 06:00 [entrez]
PHST- 2012/01/10 06:00 [pubmed]
PHST- 2012/12/18 06:00 [medline]
PHST- 2012/01/08 00:00 [pmc-release]
AID - ar3554 [pii]
AID - 10.1186/ar3554 [doi]
PST - epublish
SO  - Arthritis Res Ther. 2012 Jan 8;14(1):R6. doi: 10.1186/ar3554.