Anti-CD20 monoclonal antibody with enhanced affinity for CD16 activates NK cells at lower concentrations and more effectively than rituximab

Julie A Bowles; Siao-Yi Wang; Brian K Link; Barrett Allan; Gregory Beuerlein; Mary-Ann Campbell; David Marquis; Brian Ondek; James E Wooldridge; Brian J Smith; James B Breitmeyer; George J Weiner

doi:10.1182/blood-2006-04-020057

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Anti-CD20 monoclonal antibody with enhanced affinity for CD16 activates NK cells at lower concentrations and more effectively than rituximab

Journal article

Open access

Peer reviewed

Anti-CD20 monoclonal antibody with enhanced affinity for CD16 activates NK cells at lower concentrations and more effectively than rituximab

Julie A Bowles, Siao-Yi Wang, Brian K Link, Barrett Allan, Gregory Beuerlein, Mary-Ann Campbell, David Marquis, Brian Ondek, James E Wooldridge, Brian J Smith, …

Blood, Vol.108(8), pp.2648-2654

10/15/2006

DOI: 10.1182/blood-2006-04-020057

PMCID: PMC1895597

PMID: 16825493

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Abstract

Growing evidence indicates that the affinity of monoclonal antibodies (mAbs) for CD16 (FcgammaRIII) plays a central role in the ability of the mAb to mediate antitumor activity. We evaluated how CD16 polymorphisms, and mAb with modified affinity for target antigen and CD16, affect natural killer (NK) cell phenotype when CD20(+) malignant B cells were also present. The mAb consisted of rituximab (R), anti-CD20 with enhanced affinity for CD20 (AME-B), and anti-CD20 with enhanced affinity for both CD20 and CD16 (AME-D). Higher concentrations of mAb were needed to induce CD16 modulation, CD54 up-regulation, and antibody-dependent cellular cytotoxicity (ADCC) on NK cells from subjects with the lower affinity CD16 polymorphism. The dose of mAb needed to induce NK activation was lower with AME-D irrespective of CD16 polymorphism. At saturating mAb concentrations, peak NK activation was greater for AME-D. Similar results were found with measurement of CD16 modulation, CD54 up-regulation, and ADCC. These data demonstrate that 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 they provide further evidence for the clinical development of such mAbs with the goal of improving clinical response to mAb.

Antigens, CD - immunology

Antigens, CD20 - immunology

Up-Regulation

Antibodies, Monoclonal, Murine-Derived

Antibody-Dependent Cell Cytotoxicity

Humans

GPI-Linked Proteins

Rituximab

Receptors, IgG - immunology

Antigens, CD - genetics

Polymorphism, Genetic

DNA - genetics

Intercellular Adhesion Molecule-1 - metabolism

Receptors, IgG - genetics

Antibodies, Monoclonal - administration & dosage

Base Sequence

Killer Cells, Natural - immunology

In Vitro Techniques

Leukemia, Lymphocytic, Chronic, B-Cell - immunology

Details

Title: Subtitle: Anti-CD20 monoclonal antibody with enhanced affinity for CD16 activates NK cells at lower concentrations and more effectively than rituximab
Creators: Julie A Bowles - Department of Internal Medicine, Holden Comprehensive Cancer Center at the University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA
Siao-Yi Wang
Brian K Link
Barrett Allan
Gregory Beuerlein
Mary-Ann Campbell
David Marquis
Brian Ondek
James E Wooldridge
Brian J Smith
James B Breitmeyer
George J Weiner
Resource Type: Journal article
Publication Details: Blood, Vol.108(8), pp.2648-2654
DOI: 10.1182/blood-2006-04-020057
PMID: 16825493
PMCID: PMC1895597
NLM abbreviation: Blood
ISSN: 0006-4971
eISSN: 1528-0020
Publisher: United States
Grant note: T32 GM007337 / NIGMS NIH HHS P50 CA 97274 / NCI NIH HHS
Language: English
Date published: 10/15/2006
Academic Unit: Pharmaceutical Sciences and Experimental Therapeutics; Biostatistics; Holden Comprehensive Cancer Center; Internal Medicine
Record Identifier: 9983997313202771

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