Increasing the Potency of Antibody–Drug Conjugates

Novel linker technology enables the rapid development and manufacture of highly stable antibody–drug conjugates (ADCs) with improved safety and efficacy.

Targeted Nature Drives Interest in ADCs

ADCs are powerful biopharmaceuticals that deliver highly potent drugs very specifically to the desired target tissue. Comprising highly potent, small molecule cytotoxic agents conjugated to antibodies using various linker technologies, ADCs enable the highly selective delivery of the payload to the diseased tissue. After binding of the antibody to the targeted cells, the linker chemistry is designed to release the payload. As a result, the impact of the treatment on healthy cells is minimized, leading to reduced side effects compared with conventional chemotherapies.

The global ADC market was valued at $1.57 billion in 2017 and is projected to register a compound annual growth rate (CAGR) of 25.9% through 2025.1

Issues with Conventional Linker Technology

For ADCs to be effective, the payload must remain linked to the antibody until binding has occurred to the site of action, at which time it must be released. With many conventional linker technologies, premature loss of the drug occurs in the body owing to the unstable attachment of the drug to the antibody. Early release leads to toxicities in healthy tissue (causing side effects) and reduced overall ADC efficacy.

Many site-specific payload-conjugation technologies face development and manufacturing challenges, because they require time-consuming and costly antibody and/or cell line engineering, use linkers with limited solubility for hydrophobic payloads, which can lead to aggregation and fast blood clearance, and/or deploy unstable chemistries for payload linkage. 

Novel Linker Technology

Founded in January 2019, Araris Biotech AG is a spin-off company from the Paul Scherrer Institute (PSI) and ETH Zurich pioneering a novel site-specific ADC-linker technology. Our peptidic linker platform enables the attachment of any payload to native, “off-the-shelf” antibodies without the need for prior antibody engineering.

Most importantly, ADCs developed with the Araris linker technology have exhibited high efficacy and low levels of toxicity. 

Eliminating the requirement for antibody engineering reduces the time and cost required for ADC development. In addition, the novel linker technology is hydrophilic and offers excellent solubility, even when conjugated to highly hydrophobic payloads.

Furthermore, due to the peptidic nature of the linker, it is easy to incorporate reactive (functional) chemical groups that enable the attachment of many types of payloads (e.g., toxins, dyes, metal chelators) to different antibodies using a wide range of chemistries (e.g., azide, thiol sulfhydryl, and combinations). In fact, more than one type of payload can be conjugated to the same antibody. Regardless of the chemistry, however, ADCs with a clear drug-to-antibody-ratio (DAR) of two or four are always obtained.

Another benefit of the Araris linker technology is its compatibility with high-throughput screening, which allows for the rapid identification of the optimum antibody–payload pair. As a result, with our linker platform, payload attachment can generally be achieved in less than two days.

Most importantly, ADCs developed with the Araris linker technology have exhibited high efficacy and low levels of toxicity. In experiments conducted to date, antibody–payload combinations with the identical attachment sites but using the Araris linker technology have exhibited higher efficacy in vitro and in vivo than ADCs prepared using conventional methods. This higher performance can be attributed to the greater stability of the linkage and its attractive biophysical properties.

Two-Pronged Business Plan

Araris Biotech has several business goals. Initially, we are focused on providing pharmaceutical companies developing ADCs access to our novel linker technology, ideally through licensing agreements. In the near future, we also intend to develop our own ADC drugs for the treatment of cancer and other indications. This work is at the preliminary stage, with efforts currently directed to evaluating potential targets in oncology and other disease areas.

With respect to funding, we recently completed a seed financing round and are in active discussions with existing and potential new investors regarding a tranched Series A round. The money raised will be used to explore the full potential of our linker technology and to develop our own pipeline of ADCs.

References

  1. Antibody Drug Conjugates Market Size, Share & Trends Analysis Report By Application (Brain Tumor, Blood, Breast, Ovarian, Lung Cancer), By Technology (Cleavable, Non-cleavable Linker), And Segment Forecasts, 2019 – 2025. Rep. Grand View Research. Jan. 2019. Web.

Philipp Spycher

Philipp obtained his Master’s degree and Ph.D. from ETH Zurich (Switzerland) at the interface of material science and protein engineering. During his post-doctoral work at the Paul Scherrer Institut (PSI, Switzerland), he introduced novel enzymatic approaches for antibody conjugation that led to the discovery of the Araris Linker Technology. Philipp won the PSI Founder Fellowship as well as several other prices and grants to commercialize the technology. He is now leading Araris as CEO and managed to assemble a world-class team of co-founders and co-workers.

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