Preclinical Pharmacokinetics and Safety of Sym004: A Synergistic Antibody Mixture Directed against Epidermal Growth Factor Receptor

Abstract

Purpose: Sym004 is a novel therapeutic antibody mixture product comprising two unmarketed monoclonal antibodies (mAb) targeting the epidermal growth factor receptor (EGFR). In previous preclinical proof-of-concept studies, Sym004 was shown to elicit superior cancer cell growth inhibition activities compared with marketed anti-EGFR mAbs. This article describes the design and results of the preclinical safety program conducted to support early clinical development of Sym004.Experimental Design: Tissue cryosections from various species were stained with Sym004 to evaluate tissue cross reactivity. The pharmacokinetics of Sym004 were evaluated in a mouse xenograft model and in Cynomolgus monkeys. Monkeys received once weekly intravenous infusions of Sym004 in the range 2 to 24 mg/kg for 6 to 8 weeks. Cetuximab (a marketed anti-EGFR mAb) and the individual antibodies comprising Sym004 were included in the repeat-dose toxicity studies at single-dose level.Results: Sym004 had a staining pattern similar to cetuximab in tissue panels from both human and nonhuman primates. Once weekly dosing of Sym004 to Cynomolgus monkeys did not cause accumulation, whereas administration of the individual antibodies resulted in prolonged half-life and accumulation. In direct comparisons with cetuximab, Sym004 did not induce any distinct or novel adverse findings in the animals. However, an early onset of pronounced, reversible, and anticipated anti-EGFR-mediated pharmacologic effects, such as skin rash, dehydration, and liquid feces, was observed. Only minor adverse effects were recorded in animals treated with the individual antibodies comprising Sym004.Conclusion: Sym004 was well tolerated and did not induce any unexpected toxicities. The preclinical safety data enabled initiation of the ongoing clinical development.

Safety and Activity of the First-in-Class Sym004 Anti-EGFR Antibody Mixture in Patients with Refractory Colorectal Cancer

“…Preclinical studies with Sym004 showed both superior induction of tumor regression as compared with other EGFR-targeting antibodies and antitumor activity in models of acquired cetuximab resistance ( 7 , 17 ). Toxicology studies in cynomolgus monkeys showed a toxicity profi le consistent with other drugs of the same class, including dermatologic and gastrointestinal events ( 19 ).…”

“…The starting dose of the dose-escalation cohort was derived based on a recently published toxicology study in cynomolgus monkeys ( 19 ). Patients were enrolled sequentially, and cohorts received weekly doses of 0.4, 0.75, 1.5, 3, 6, 9, or 12 mg/kg; 1 patient in the 2 fi rst cohorts followed by 3 to 6 patients in subsequent cohorts according to the traditional 3+3 design.…”

Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3

“…151 Sym004, a therapeutic antibody mixture comprising several mAbs targeting EGFR, was shown to elicit superior cancer cell inhibition and has already completed safety trials. 152 Using cellular models, it was shown that Sym004 might overcome acquired resistance to cetuximab. 153 In line with this, preclinical 154 data supported tumor dependency on EGFR signaling.…”

Potential therapeutic roles for antibody mixtures

“…There are at least eight different examples of antibody mixtures that are currently in clinical development [1]. These antibody mixtures may provide advantages over antibody monotherapy because the individual antibody components present in the mixture may complement each other to target the diseases (Table 1) [17]. For example, Xoma is developing an antibody mixture containing three antibodies to target and neutralize the toxin from botulism poisoning [15][16][17].…”

“…For example, Xoma is developing an antibody mixture containing three antibodies to target and neutralize the toxin from botulism poisoning [15][16][17]. Xoma 3AB, which is a lyophilized formulation of three different antibodies in equimolar proportions directed against three distinct domains on the BoNT/A neurotoxin protein, is an example of an antibody mixture against a single antigen [15][16][17].…”