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Adnectin Conjugates for Cancer Therapy and Imaging
Developing A Conjugation-Based Multivalent Ab Format
Beyond ADC’s - Advances in New Linkers and Higher Drug Payloads
Adnectins are a family of engineered target-binding proteins based on the 10th human fibronectin type III domain. We will describe the properties of Adnectin-drug conjugates and Adnectin-based PET imaging agents, both of which rely on a combination of high affinity for a therapeutically relevant target and fast clearance from tissues free of the target.
Abdurins are an antibody-like scaffold platform derived from the CH2 domain of Fc, retain FcRn-binding, leading to a prolonged circulating half-life. The small size coupled with long half-life facilitates better tissue/tumor penetration and higher target drug concentrations. Recent studies demonstrate that Abdurin-drug conjugates can increased the Therapeutic Index and safely and more effectively deliver toxic payloads in a xenograft model.
We present a novel ADC format based on the site-specific conjugation of a derivative of the anthracycline PNU-159682 using the transpeptidase Sortase A. The use of a non-cleavable peptide linker provides exquisite stability in vivo, whereas the anthracycline payload endows the ADC with superior potency combined with attractive immune-oncology properties intrinsic to this class of payloads. Validating data obtained in numerous PDX models, as well as in immunocompetent syngeneic models, will be presented.
Novel Conjugation Techniques to Improve Selectivity, Yield and Stability
We describe a novel multivalent format based on protein conjugation (TRACS). The building blocks are mAbs and Fabs with good expression yields and stability. A conjugation site that supports high conjugation rates and an efficient process was identified. The spatial arrangement of all the Fabs allows their simultaneous binding with reduced steric hindrance. We provide examples of different TRACS that require concurrent binding of all Fabs for their biological activity.
The use of automated high throughput screening in large molecule discovery research still lags behind that of small molecule discovery. Here, we developed a magnetic bead-based approach for antibody capture and conjugation, together with an automated platform to complete a bioconjugation optimization. Given LC-MS is a widespread analytical bottleneck, we also established a high-throughput MS platform to accurately detect and rapidly quantitate ADCs with acquisition time of 20 sec/sample, 10-50x improvement over traditional LC-MS methods.
First generation ADCs suffer from heterogeniety issues which can cause efficacy issues along with toxicity. We set out to design a second generation conjugation technology that increased stability and efficacy. This second generation ADC platform allows increased homogeniety without using site directed technologies.
To enable duocarmycin dimers as payloads for ADCs we investigated various locations on the drug for linker attachment. The use of structure-based drug design facilitated this process and led to highly efficacious conjugates. The impacts of these changes on both efficacy and toxicity will be discussed.