Fulfilling the Promise of Centyrins from Protein Design to Patients
Aro Biotherapeutics is harnessing its Centyrin protein platform to develop therapies that change the course of treatment for the most devastating diseases. Centyrins can be readily expressed in mono-, bi-, or tri-specific formats, enabling recognition and modulation of multiple target antigens on tumors or immune cells to achieve the desired therapeutic effect. We are building a product pipeline that will focus on the development of novel medicines that will enable targeted delivery of next-generation drug payloads to virtually any cell type. This includes oligonucleotide therapeutics, small molecule combinations, Centyrin-drug conjugates and Centyrin-lipid nanoparticles, with an initial focus in oncology and immunology.
Our strategy also includes development of partnerships that couple Centyrin technology with delivery of a variety of drug payloads to build a pipeline of new therapies for diverse diseases with high unmet needs.
cMET:EGFR Bi-specific Centyrin Program
Aro is currently in late-stage discovery of a bi-specific Centyrin that targets the cMET receptor and the epidermal growth factor receptor (EGFR), which cooperate to drive tumor cell proliferation and have been linked to a variety of human cancers, including non-small cell lung cancers (NSCLCs), squamous cell carcinoma of the head and neck and gastrointestinal cancers. Several generations of EGFR tyrosine kinase inhibitors (TKIs) are used to treat metastatic NSCLC in patients with EGFR mutations; however, all patients eventually regress due to additional mutations in one or more genes. Mutations in the cMET pathway have been identified as an important mechanism for resistance to EGFR TKIs.
Creating the Optimal Bi-specific Centyrin
The cMET:EGFR bi-specific Centyrin offers the potential for improved anti-tumor activity and selective targeting of tumor vs normal cells due to avidity and bi-specificity, while demonstrating activity against tumors with various resistance mechanisms in these pathways. The cMET:EGFR bi-specific Centyrin has shown promise in preclinical tumor models. Our lead molecules in the ABX900 series are expressed with a third Centyrin domain that recognizes a human serum protein to extend the half-life in patients.
cMET:EGFR Bi-specific for Advanced NSCLC
Estimated incidence of advanced NSCLC (Stage IIIB/IV) is ~110,000 in the U.S. and over 155,000 in ROW. Many patients who are diagnosed have advanced disease.*
1st, 2nd or 3rd generation EGFR TKIs approved for treatment of patients with advanced disease and EGFR mutations
cMET mutations can be primary or acquired with EGFR TKI treatment
Dual inhibition of cMET and EGFR pathways offers potential for more effective treatment of advanced NSCLC
The cMET:EGFR bi-specific Centyrin offers the potential for improved anti-tumor activity and selective targeting of tumor vs normal cells due to avidity and bi-specificity, while demonstrating cytotoxicity vs cell lines with EGFR or cMET mutations in the nM to sub nM range, as well as superior potency and activity vs 1st, 2nd and 3rd generation approved TKIs. The cMET:EGFR Centyrin has shown promise in preclinical tumor models. Our lead series, ABX900, are designed to extend the half life in patients by including a third Centyrin domain that binds a human serum protein. The ABX900 series express at high levels as soluble proteins in E. coli enabling development of efficient and cost - effective manufacturing.
Centyrin siRNA conjugates, undisclosed targets
With the combination of biophysical properties and specificity in cell targeting, Centyrins are poised to build the next generation of protein therapeutics for targeted delivery of drug payloads to specific disease sites. We have developed an efficient screening cascade that identifies high affinity, internalizing Centyrins directed to receptors on tumors, and have established multiple approaches for chemical conjugation of drug payloads to specific Centyrin amino acid residues enabling intracellular delivery and specific in vitro and in vivo activity.
Screening Cascade for Centyrin-Targeted Drug Delivery
The ABX200 discovery program is focused on delivering Centyrin – siRNA drug conjugates to tumors. We are also designing receptor – specific Centryins for drug delivery to other tissues including muscle, CNS, and immune cells.
Centyrins are designed to enable tissue – specific delivery of nucleic acids and other drug conjugates
siRNAs directed to hepatic targets are a clinically validated drug class, but delivery to extra-hepatic targets remain a challenge to the field
siRNAs have potential to address previously undruggable targets by targeting mRNA
Centyrin properties enable site specific conjugation of drug payloads, binding and internalization to cell surface targets, thereby delivering drug payloads to the intended disease site
*Fore Pharma, Global Non-Small Cell Lung Cancer Epidemiology and Patient Flow – 2018, Aug 2018.