Treatment with the C5a receptor antagonist ADC-1004 reduces myocardial infarction in a porcine ischemia-reperfusion model

Abstract

BackgroundPolymorphonuclear neutrophils, stimulated by the activated complement factor C5a, have been implicated in cardiac ischemia/reperfusion injury. ADC-1004 is a competitive C5a receptor antagonist that has been shown to inhibit complement related neutrophil activation. ADC-1004 shields the neutrophils from C5a activation before they enter the reperfused area, which could be a mechanistic advantage compared to previous C5a directed reperfusion therapies. We investigated if treatment with ADC-1004, according to a clinically applicable protocol, would reduce infarct size and microvascular obstruction in a large animal myocardial infarct model.MethodsIn anesthetized pigs (42-53 kg), a percutaneous coronary intervention balloon was inflated in the left anterior descending artery for 40 minutes, followed by 4 hours of reperfusion. Twenty minutes after balloon inflation the pigs were randomized to an intravenous bolus administration of ADC-1004 (175 mg, n = 8) or saline (9 mg/ml, n = 8). Area at risk (AAR) was evaluated by ex vivo SPECT. Infarct size and microvascular obstruction were evaluated by ex vivo MRI. The observers were blinded to the treatment at randomization and analysis.ResultsADC-1004 treatment reduced infarct size by 21% (ADC-1004: 58.3 ± 3.4 vs control: 74.1 ± 2.9%AAR, p = 0.007). Microvascular obstruction was similar between the groups (ADC-1004: 2.2 ± 1.2 vs control: 5.3 ± 2.5%AAR, p = 0.23). The mean plasma concentration of ADC-1004 was 83 ± 8 nM at sacrifice. There were no significant differences between the groups with respect to heart rate, mean arterial pressure, cardiac output and blood-gas data.ConclusionsADC-1004 treatment reduces myocardial ischemia-reperfusion injury and represents a novel treatment strategy of myocardial infarct with potential clinical applicability.

Complement in Immune and Inflammatory Disorders: Therapeutic Interventions

“…Novo Nordisk is developing two anti-C5aR antibodies (Table 1) and is conducting phase I trials for rheumatoid arthritis (NCT01223911, NCT01611688). A protein antagonist based on the immune evasion protein CHIPS from S. aureus (ADC-1004, Alligator Bioscience) had been tested in a myocardial IRI model, in which it reduced infarct size by 21% (75), but the company has announced a delay in further development of this compound. Compared with C5aR, therapeutic modulation of C3a receptor (C3aR) has proven challenging and a C3aR antagonist candidate (SB 290157) showed partial agonism (76).…”

A vital role for complement in heart disease

“…Animal models have emphasized the importance of the complement system in myocardial infarction, and pharmacological inhibition of the complement system has also shown promising results in experimental studies (del Balzo et al, 1985;Weisman et al, 1990;Fairweather et al, 2006;van der Pals et al, 2010;Mueller et al, 2013).…”

International Union of Basic and Clinical Pharmacology. LXXXVII. Complement Peptide C5a, C4a, and C3a Receptors

“…The C5a 1 receptor is bound by CHIPS at the N terminus, at a site that overlaps with the C5a binding, meaning that CHIPS is a potent antagonist for the C5a 1 receptor (K d = 1.1 nM) (de Haas et al, 2004;Haas et al, 2004;Postma et al, 2004Postma et al, , 2005Ippel et al, 2009). CHIPS is too immunogenic for therapeutic use (Wright et al, 2007), but ADC-1004, a derivative of CHIPS produced by directed evolution, has minimal immunogenicity and may have therapeutic potential (Gustafsson et al, 2009a(Gustafsson et al, ,b, 2010van der Pals et al, 2010). More recently, a smaller peptide derivative of CHIPS has been reported (Bunschoten et al, 2011).…”