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In Vitro Methods for Comparing Target Binding and CDC Induction Between Therapeutic Antibodies: Applications in Biosimilarity Analysis
Published on: May 4, 2017
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Block-Removed Immunoglobulin Technology to enhance rituximab effector function by counteracting CA125-mediated
Luigi Grasso1, James Bradford Kline1, Nicholas C Nicolaides1
1Navrogen Inc., Cheyney, PA 19319, USA.
Oncology Letters
|November 25, 2021
Summary
Cancer antigen 125 (CA125) interferes with rituximab (RTX) efficacy in non-Hodgkin Lymphoma (NHL). A new RTX variant, NAV-006, shows improved tumor cell killing, offering potential for NHL patients with high CA125 levels.
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- Rituximab (RTX) is a standard therapy for non-Hodgkin Lymphoma (NHL), targeting CD20.
- High serum levels of cancer antigen 125 (CA125) negatively impact RTX effectiveness in a significant portion of follicular lymphoma patients.
- RTX exerts anti-cancer effects through complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC).
Purpose of the Study:
- To investigate the mechanism by which CA125 affects RTX activity.
- To develop novel RTX variants with enhanced efficacy in the presence of CA125.
- To identify a CA125-refractory RTX variant for improved NHL treatment.
Main Methods:
- Cellular and molecular analyses were performed to study RTX and CA125 interactions.
- A proprietary Block-Removed Immunoglobulin Technology was used to generate RTX variants.
- High-throughput functional screenings were employed to identify CA125-refractory RTX variants.
Main Results:
- CA125 was found to bind to RTX, diminishing its tumor cell killing capabilities.
- A novel RTX variant, NAV-006 (RTX-N109D), demonstrated reduced interaction with CA125.
- NAV-006 exhibited increased ADCC and CDC activities compared to the parent RTX, indicating reduced susceptibility to CA125-mediated immunosuppression.
Conclusions:
- CA125 directly interferes with RTX's anti-tumor activity in NHL.
- NAV-006 represents a promising next-generation anti-CD20 antibody.
- NAV-006 has the potential to overcome CA125-induced resistance and improve RTX efficacy in NHL patients with elevated CA125 levels.
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