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Determination of the Relative Potency of an Anti-TNF Monoclonal Antibody (mAb) by Neutralizing TNF Using an In Vitro Bioanalytical Method
Published on: September 16, 2017
Inactivation of TNF signaling by rationally designed dominant-negative TNF variants
Paul M Steed1, Malú G Tansey, Jonathan Zalevsky
1Xencor, 111 West Lemon Avenue, Monrovia, CA 91016, USA.
Science (New York, N.Y.)
|September 27, 2003
Summary
Scientists engineered variant tumor necrosis factor (TNF) proteins to neutralize native TNF. This strategy inactivates TNF by sequestration, offering a potential new approach for anti-inflammatory biotherapeutics.
Area of Science:
- Biochemistry
- Immunology
- Structural Biology
Background:
- Tumor necrosis factor (TNF) is a critical regulator of inflammation.
- Dysregulated TNF signaling is implicated in numerous pathological conditions.
- Targeting TNF is a key strategy in treating inflammatory diseases.
Purpose of the Study:
- To engineer variant TNF proteins capable of inhibiting native TNF activity.
- To develop a novel strategy for inactivating TNF through protein complex formation.
- To explore the potential of dominant-negative TNF variants as anti-inflammatory biotherapeutics.
Main Methods:
- Structure-based protein design was employed to engineer novel TNF variants.
- The engineered variants were designed to form heterotrimers with native TNF.
- The functional consequence of these heterotrimers on TNF receptor binding and signaling was assessed.
Main Results:
- Engineered TNF variants rapidly form heterotrimeric complexes with native TNF.
- These complexes effectively sequester native TNF, preventing receptor binding.
- The strategy demonstrated attenuation of TNF-mediated pathology in animal models.
- The engineered dominant-negative TNFs showed potential as anti-inflammatory agents.
Conclusions:
- Dominant-negative TNF variants can be rationally designed to inhibit TNF function.
- TNF inactivation via sequestration presents a viable therapeutic strategy for inflammatory conditions.
- This approach may be extendable to other multimeric cytokines within the TNF superfamily.
