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Mike Schopperle, PhD
Development of Antibody-Drug-Conjugates to Novel Embryonic Targets in Cancer
In this presentation, we will describe the development of a conjugate approach employing Cys-engineered antibodies and XTEN® polypeptides to enable the preparation of homogeneous ADCs with high drug load (>14), exceptional pharmacokinetics and anti-tumor efficacy. Considerations for the application to the delivery of non-conventional payloads will be discussed.
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Nanotechnology provides for a promising platform in the development of next-generation antibody drug conjugates, which we refer to as antibody-directed nanotherapeutics (ADNs). Due to the formidable size of these nanocarriers (~100 nm), the preferential accumulation in solid tumors provides for a second layer of targeting or specificity compared to smaller antibody drug conjugates where the drug is covalently linked directly to the antibody. The active drug is also only noncovalently associated with the nanocarrier in the ADN format, allowing for precise control of release rate or dissociation from the formulation through control of the lipid composition and an active electrochemical gradient that retains the drug in the liposomal interior.
Antigen-Targeted Amanitin-Conjugates (ATACs) represent a new class of ADCs using the payload Amanitin. This payload introduces a novel mode of action into oncology therapy, the inhibition of RNA polymerase II. The technology platform includes Amanitin supply, site-specific conjugation, demonstrated safety profile and biomarker. HDP-101 is the first ATAC directed against BCMA entering Phase I trials by the end of 2019.
Half-life extension technologies such as PEGylation and albumin-binding domains (ABDs) have been widely used to improve the pharmacokinetics of many different types of biologics. In this study, we used an anti-5T4 diabody conjugated with a highly potent cytotoxic pyrrolobenzodiazepine (PBD) warhead to assess and compare the effects of PEGylation and albumin binding on the in vivo efficacy of antibody fragment drug conjugates
MM-201 is a TRAIL agonist consisting of an IgG1 Fc fused to a single chain TRAIL trimer with additional stabilizing mutations that were identified using yeast display. MM-201 has improved pharmacokinetic properties, and greater apoptotic activity compared to the ABBV621 competitor molecule both in vitro and in vivo in colorectal carcinoma and sarcoma cell lines and mouse xenograft models. We believe that MM-201 when combined with an appropriate patient selection strategy will result in favorable clinical outcomes.
This presentation will focus on engineering multiple properties of monoclonal antibodies to maximize the therapeutic window. Properties such as conjugation location, antibody internalization, antibody affinity, drug and linker type, and use of dual payloads will be discussed.
Cellular reprogramming or de-differentiation is an emerging concept for the origin and development of aggressive and metastatic cancers. Reprogramming leads to malignant cells with primitive characteristics and embryonic gene signatures. We have developed therapeutic antibody-drug-conjugates specific to embryonic targets not expressed in normal tissues and re-expressed in cancer.
We have been developing several ADCs, such as DS-8201a and U3-1402a, which showed a potent and broad spectrum of anti-tumor activity both in preclinical and clinical. Our ADC technology has unique features; stable linker, high clearance of the payload, high DAR, and bystander effect. I will review our ‘smart chemo’ ADC technology and discuss the features as next generation ADC technology.