Adalimumab p55 p75 TNF receptor binding

Adalimumab does not directly bind to p55 or p75 TNF receptors; instead, it binds to TNFα and sterically blocks TNFα from engaging these receptors.

Abstract

No studies directly measured adalimumab binding to isolated p55 (TNF-RI) or p75 (TNF-RII) receptors. Instead, adalimumab exerts its effects by binding to TNFα with high affinity (30.4 pM) and sterically blocking TNFα-receptor interactions through epitope overlap with the TNFR2 binding site. The adalimumab epitope comprises discontinuous TNFα segments, competitively inhibiting TNFα binding to both receptor subtypes and preventing activation of downstream signaling pathways including NF-κB.

Methods

We analyzed 10 sources from an initial pool of 200, using 7 screening criteria. Each paper was reviewed for 6 key aspects that mattered most to the research question.

Paper search

We performed a semantic search across over 138 million academic papers from the Elicit search engine, which includes all of Semantic Scholar and OpenAlex. The search returned 200 total results from Elicit.

Screening

We screened in sources based on their abstracts that met several criteria, including:

• Adalimumab Binding Mechanisms
• Specific TNF Receptor Types
• Binding Measurements
• Appropriate Study Design
• Mechanistic Data Inclusion
• Adalimumab Focus
• Study Type Quality

Data extraction

We extracted data regarding:

• TNF Receptor Binding Data
• Receptor Expression Effects
• Binding Mechanism
• Functional Consequences
• Experimental Methods
• Comparative Analysis

Results

Characteristics of Included Studies

The review included 10 studies examining adalimumab’s interactions with TNF receptors, published between 2009 and 2022.

Binding Characteristics and Epitope Mapping

Adalimumab demonstrated binding affinity to TNFα with KD values ranging from 7.05 × 10^-11 M to 1.0 × 10^-10 M. Crystal structure analysis identified the adalimumab epitope on TNFα with a total buried surface area of 2,540 Ų, indicating that adalimumab competitively inhibits the binding of TNFR to TNFα.

Effects on TNF Receptor Expression and Function

Studies revealed that adalimumab maintained TNF-RI at baseline levels while TNF reduced it 2.4-fold. Adalimumab's binding prevented TNFR activation involved in signaling pathways such as NF-κB, and completely inhibited TNF-induced apoptosis in a dose-dependent manner.

Comparative Analysis with Other TNF Inhibitors

Binding Characteristics Comparison

Binding affinity measurements revealed differences among TNF inhibitors. Adalimumab demonstrated a binding affinity of 30.4 pM, compared to infliximab at 27.3 pM and etanercept at 11.8 pM. The epitope overlap with the TNFR2 binding site was more substantial for adalimumab compared to infliximab.

Functional Superiority

Adalimumab preserved 100% of TNF-RI, while other agents like etanercept and infliximab were less effective.

Synthesis

The reviewed studies indicate that adalimumab blocks TNF receptor signaling primarily through competitive inhibition rather than direct receptor binding. The differential preservation of TNF-RI versus TNF-RII by adalimumab suggests a receptor-specific mechanism that is clinically relevant for maintaining pro-inflammatory and apoptotic signals.