Pioneering the application of mAb mixtures
We are pioneering the application of mAb mixtures as a differentiated approach to cancer therapy that can overcome some of the limitations of conventional single-target mAbs. A mAb mixture is a combination of two or more systematically selected, well-characterized mAbs developed as a single drug product.
The mAbs in our mixtures may bind different positions on the same target or they may bind different targets. The targets can be on the same or on diverse cell types. Targets are typically cell-surface receptors or ligands. Our mAb mixtures may also be combined with immune checkpoint inhibitors or in combination with other treatment approaches.
mAb mixtures are advantageous compared to traditional mAbs as they provide both specificity and diversity. Diversity is essential in cancer treatment due to the rapid evolution of treatment resistance and evidenced by the rising number of product candidates combining multiple therapeutics. Due to their diversity, mAb mixtures have the potential to delay or address treatment resistance by synergistic target inhibition or activation, being less sensitive to mutations destroying the antibody binding site, and by addressing heterogeneity of tumors.
mAb mixtures for RTK inhibition
Our proprietary mAb mixture product candidates consist of pairs of synergistic antibodies designed to bind non-overlapping epitopes on the extra-cellular ligand binding part of a particular RTK. Upon binding the RTK, the antibody pair induces cross-linking of the receptor, which in turn triggers internalization and degradation of the receptor-antibody complex. The result is rapid elimination of the oncogenic RTK from the cancer cells, effective receptor inhibition and prevention of tumor growth, as seen in the figure below.
Receptor elimination is an effective mechanism for inhibiting RTK activity and the figure on the right below charts data from a preclinical model comparing Sym004 to the two individual antibodies: 992 (futuximab) and 1024 (modotuximab) constituting the Sym004 mixture as well as the current market-leading anti-EGFR antibody Erbitux® (cetuximab). The Sym004 product induces a pronounced synergistic and durable tumor growth inhibition while the single mAbs only slow down tumor growth.
Publications
Sym015: A highly efficacious antibody mixture against MET amplified tumors
PMID: 28679766 [PubMed - as supplied by publisher]
Efficacy of Sym004 in Patients With Metastatic Colorectal Cancer With Acquired Resistance to Anti-EGFR Therapy and Molecularly Selected by Circulating Tumor DNA Analyses
The First-in-class Anti-EGFR Antibody Mixture Sym004 Overcomes Cetuximab Resistance Mediated by EGFR Extracellular Domain Mutations in Colorectal Cancer
Phase I dose-escalation trial of Sym004, a mixture of two anti-EGFR antibodies, in Japanese patients with advanced solid tumors
Pan-HER, an Antibody Mixture Simultaneously Targeting EGFR, HER2, and HER3, Effectively Overcomes Tumor Heterogeneity and Plasticity
A proof of concept trial of the anti-EGFR antibody mixture Sym004 in patients with squamous cell carcinoma of the head and neck.
Safety and Activity of the First-in-Class Sym004 Anti-EGFR Antibody Mixture in Patients with Refractory Colorectal Cancer
Sym004, a novel anti-EGFR antibody mixture, augments radiation response in human lung and head and neck cancers
Sym004, a novel EGFR antibody mixture, can overcome acquired resistance to cetuximab
Rational identification of an optimal antibody mixture for targeting the epidermal growth factor receptor
Preclinical pharmacokinetics and safety of Sym004: a synergistic antibody mixture directed against epidermal growth factor receptor
Sym004: A Novel Synergistic Anti–Epidermal Growth Factor Receptor Antibody Mixture with Superior Anticancer Efficacy