GZ402668, a next-generation anti-CD52 antibody, binds to a unique epitope on human CD52 and displays decreased cytokine release
Author(s): ,
W.M. Siders
Affiliations:
Genzyme, a Sanofi Company, Framingham, MA, United States
,
R. Wei
Affiliations:
Genzyme, a Sanofi Company, Framingham, MA, United States
,
B. Greene
Affiliations:
Genzyme, a Sanofi Company, Framingham, MA, United States
,
A. McVie-Wylie
Affiliations:
Genzyme, a Sanofi Company, Framingham, MA, United States
,
M. Bailey
Affiliations:
Genzyme, a Sanofi Company, Framingham, MA, United States
,
V. Dhawan
Affiliations:
Genzyme, a Sanofi Company, Framingham, MA, United States
,
A. Best
Affiliations:
Genzyme, a Sanofi Company, Framingham, MA, United States
,
W. Brondyk
Affiliations:
Genzyme, a Sanofi Company, Framingham, MA, United States
,
E. Havari
Affiliations:
Genzyme, a Sanofi Company, Framingham, MA, United States
,
M.J. Turner
Affiliations:
Genzyme, a Sanofi Company, Framingham, MA, United States
,
B.L. Roberts
Affiliations:
Genzyme, a Sanofi Company, Framingham, MA, United States
,
J.M. Kaplan
Affiliations:
Genzyme, a Sanofi Company, Framingham, MA, United States
R. Sendak
Affiliations:
Genzyme, a Sanofi Company, Framingham, MA, United States
ECTRIMS Online Library. Siders W. 10/09/15; 115234; 1329
William Siders
William Siders
Contributions
Abstract
Abstract: EP1448

Type: e-Poster

Abstract Category: Immunomodulation / Immunosuppression

Background: Alemtuzumab is an anti-CD52 humanised monoclonal antibody that causes depletion of circulating lymphocytes followed by a distinctive pattern of repopulation. A next-generation anti-CD52 antibody is currently being developed to potentially decrease immunogenicity, improve the infusion-associated reaction profile, and explore the subcutaneous route of administration while maintaining efficacy.

Goals: To characterise the binding of GZ402668 to the human CD52 protein and assess its in vitro and in vivo biological activity.

Methods: The CD52 epitope recognised by GZ402668 was identified using alanine scanning mutagenesis. Crystallography analysis was also used to characterise the binding interaction. In vitro studies included a human whole blood cytokine release assay and assessment of lymphocyte cytolysis. Lymphocyte depletion was also characterised in vivo in the human CD52 transgenic mouse.

Results: Compared to alemtuzumab, GZ402668 bound to a different portion of human CD52, resulting in an interaction with different physical characteristics. In in vitro assays, GZ402668 achieved levels of lymphocyte depletion equivalent to those obtained with alemtuzumab but with slower kinetics of lysis. This was correlated with significantly lower levels of cytokine release in the human whole blood assay. Similarly, administration of GZ402668 to human CD52 transgenic mice resulted in dose-dependent lymphocyte depletion that reached levels comparable to those seen with alemtuzumab.

Conclusions: A next-generation anti-CD52 antibody has been generated that binds a different epitope on CD52. The antibody achieves similar levels of lymphocyte depletion as alemtuzumab but with reduced cytokine release in vitro. Thus, administration of GZ402668 to MS patients may result in an improved infusion-associated reaction profile. A phase 1 study in MS patients is currently underway (NCT02282826).

Disclosure: Study supported by Genzyme, a Sanofi company. All authors are employees of Genzyme/Sanofi.

Abstract: EP1448

Type: e-Poster

Abstract Category: Immunomodulation / Immunosuppression

Background: Alemtuzumab is an anti-CD52 humanised monoclonal antibody that causes depletion of circulating lymphocytes followed by a distinctive pattern of repopulation. A next-generation anti-CD52 antibody is currently being developed to potentially decrease immunogenicity, improve the infusion-associated reaction profile, and explore the subcutaneous route of administration while maintaining efficacy.

Goals: To characterise the binding of GZ402668 to the human CD52 protein and assess its in vitro and in vivo biological activity.

Methods: The CD52 epitope recognised by GZ402668 was identified using alanine scanning mutagenesis. Crystallography analysis was also used to characterise the binding interaction. In vitro studies included a human whole blood cytokine release assay and assessment of lymphocyte cytolysis. Lymphocyte depletion was also characterised in vivo in the human CD52 transgenic mouse.

Results: Compared to alemtuzumab, GZ402668 bound to a different portion of human CD52, resulting in an interaction with different physical characteristics. In in vitro assays, GZ402668 achieved levels of lymphocyte depletion equivalent to those obtained with alemtuzumab but with slower kinetics of lysis. This was correlated with significantly lower levels of cytokine release in the human whole blood assay. Similarly, administration of GZ402668 to human CD52 transgenic mice resulted in dose-dependent lymphocyte depletion that reached levels comparable to those seen with alemtuzumab.

Conclusions: A next-generation anti-CD52 antibody has been generated that binds a different epitope on CD52. The antibody achieves similar levels of lymphocyte depletion as alemtuzumab but with reduced cytokine release in vitro. Thus, administration of GZ402668 to MS patients may result in an improved infusion-associated reaction profile. A phase 1 study in MS patients is currently underway (NCT02282826).

Disclosure: Study supported by Genzyme, a Sanofi company. All authors are employees of Genzyme/Sanofi.

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