Abstract
Anti-CD20 Monoclonal Antibody (mAb) with Enhanced Affinity for CD16 Activates NK Cells at Lower Concentrations and More Effectively Than Rituximab
Blood, Vol.106(11), pp.348-348
11/16/2005
DOI: 10.1182/blood.V106.11.348.348
Abstract
Abstract
Growing evidence indicates the affinity of mAb for CD16 (FcgRIII) plays a central role in the ability of the mAb to mediate anti-tumor activity. Both polymorphisms in CD16 and structure of mAb Fc can impact on the affinity between CD16 and mAb. Little is known about how affinity between mAb and CD16 impacts on the ability of mAb to activate NK cells. We evaluated how CD16 polymorphisms, and mAb with modified affinity for CD16, impact on NK cell phenotype and cytokine production. MAb consisted of R, anti-CD20 with enhanced affinity for CD20 (AME-133), and AME-133 with Fc engineered to have enhanced affinity for both CD20 and CD16 (Fc-eng-133). Peripheral blood mononuclear cells were obtained from normal subjects that were homozygous for high affinity CD16 (VV at position 158), homozygous low affinity (FF at 158), and heterozygotes and were mixed with mAb and Raji lymphoma cells at an effector:target ratio of 1:1. Higher concentrations of mAb were needed to induce CD16 modulation, CD54 upregulation, and IFNg production on NK cells from subjects with the lower affinity CD16 polymorphism. The dose of mAb needed to induce NK activation was lower with Fc-eng-133 irrespective of CD16 polymorphism.
Measure of activation - % of NK cells CD54 bright: EC50 ng/ml (mean moAb concentration +/− SEM): N=4 per polymorphism
R AME-133 Fc-eng-133 p<0.01 - R vs AME-133; R vs Fc-eng-133; AME-133 vs Fc-eng-133 for each polymorphism VV 6.2 +/− 1.0 3.9 +/− 0.5 1.0 +/− 0.3 VF 11.6 +/− 1.7 5.7 +/− 0.6 1.4 +/− 0.4 FF 29.9 +/− 10.6 11.5 +/− 2.5 2.8 +/− 0.3 p value VV vs FF <0.05 <0.05 <0.05
At saturating mAb concentrations, peak NK activation was greater for Fc engineered AME-133 when compared to R mAb for all samples studied
Ratio of Fc-eng-133 to R % NK cells CD54 bright 1.35 +/− 0.07 IFNg production 2.64 +/− 0.43
These data indicate tumor cells coated with mAb with enhanced affinity for CD16 are more effective at activating NK cells at both low and saturating mAb concentrations irrespective of CD16 polymorphism, and provide further evidence for the clinical development of such mAb with the goal of improving clinical response to mAb.
Details
- Title: Subtitle
- Anti-CD20 Monoclonal Antibody (mAb) with Enhanced Affinity for CD16 Activates NK Cells at Lower Concentrations and More Effectively Than Rituximab
- Creators
- George J. Weiner - University of IowaJulie A. Bowles - Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USABrian K. Link - University of IowaMary A. Campbell - Applied Molecular Evolution, San Diego, CA, USAJames E. Wooldridge - University of IowaJames B. Breitmeyer - Applied Molecular Evolution, San Diego, CA, USA
- Resource Type
- Abstract
- Publication Details
- Blood, Vol.106(11), pp.348-348
- DOI
- 10.1182/blood.V106.11.348.348
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Language
- English
- Date published
- 11/16/2005
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine; Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984362309702771
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