Background/Purpose: The cytokine tumor necrosis factor (TNF)alpha is a potent pro-inflammatory mediator involved in several autoimmune diseases including rheumatic arthritis and for over a decade has been a target of numerous biological therapies.  CEP-37247 is a bivalent anti-TNF-alpha domain antibody (dAb) construct combining the antigen-recognition function of a dAb with the pharmacological advantages of human immunoglobulin-G Fc region.  In order to assess the therapeutic applicability of CEP-37247 in comparison to other marketed anti-TNF-alpha biologics, we performed head-to-head comparisons to approved reference agents in the well established human-TNF-alpha over expressing transgenic mouse model (Tg197) that develops spontaneous rheumatoid arthritis.

Methods: Symptomatic, arthritic animals were treated in a semi-therapeutic manner starting from week-3, at disease onset.  Animals (N=8/group, male and female combined) were treated ip, twice weekly with either CEP-37247 at 30, 10, 3 or 0.3 mg/kg or reference agent Remicade at 10 or 3 mg/kg, Enbrel or Humira both at 10 mg/kg; untreated control included isotype Ab IgG₁at 10 mg/kg.  Animals were monitored for changes in body weight and clinical disease score; end measurements included serum PK/PD and histopathology.

Results: CEP-37247 provided a dose dependent, and significant (p<0.01), effect on mean arthritic scores by week 10 of disease with 0.3 mg/kg providing an effect similar to isotype control.  CEP-37247 at 30 mg/kg significantly reduced (85%, p<0.001) arthritic disease score of treated animals from onset until week 10 of age as compared to isotype control with no significant difference between dose matched groups of Remicade, Humira or Enbrel (p>0.05).  Histopathology of blinded scored H+E stained sections revealed that the isotype control had extensive cartilage destruction, bone erosion and synovial infiltrates as expected from an untreated animal; CEP-37247 impact on joint pathology mirrored that of the disease score with 30, 10 and 3 mg/kg all providing significant reduction in damage and inflammation (p<0.01) below that of isotype control, however no difference in dose matched groups compared to reference agents.    Serum CEP-37247 levels correlated with in vivo efficacy and ex vivo cytokine responses (e.g., reduction in IL-1-beta).

Conclusion: These data demonstrate the clear efficacy of a potent anti-human TNF-alpha domain antibody construct to suppress active disease in a humanized mouse model of rheumatoid arthritis as compared head-to-head against available anti-TNF-alpha therapies on the market.  At half the size of a conventional Ab but with full functionality CEP-37247 may provide the benefits of lower cost of production, immunogenicity and improved tissue distribution.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-human-tnf-alpha-domain-antibody-construct-cep-37247placulumab-is-as-efficacious-as-other-leading-tnf-alpha-blockade-therapies-in-a-humanized-mouse-model-of-rheumatoid-arthritis/