New ADC payload strategies are needed to address emerging drug resistance and limited treatment durability. Degrader-Antibody Conjugates (DACs) could significantly expand the number of druggable payload targets; however, conjugation and identification of suitable degraders remain challenging. Here, we report a new DAC platform ensuring excellent DAC stability antibody-mediated delivery of functional degraders enabling long-lasting responses even after single-dose injections in preclinical animal models.

Degrader Antibody Conjugates (DACs) represent a novel therapeutic approach that combines the specificity of antibodies with the potency of protein degraders. The design and optimization of DACs involve careful consideration of factors such as antibody selection, linker chemistry, and TPD potency. By precisely engineering these components, researchers aim to create highly effective and selective DACs for the treatment of various diseases, including cancer.

Targeted protein degradation has emerged as a promising therapeutic strategy for addressing challenging molecular pathologies. However, achieving tissue selectivity remains challenging. The PROxAb Shuttle approach introduces a non-covalent platform for antibody-mediated targeted delivery of degraders. By enhancing pharmacokinetics and prolonging degrader half-lives from hours to days, this system aims to improve the selectivity and efficacy of tumor-targeting therapies, facilitating significant anti-tumor responses in vivo.

Trastuzumab deruxtecan, utilizing DXd ADC technology, is transforming HER2 treatment by demonstrating strong efficacy not only in HER2-high, but also in HER2 ultra-low cases. Daiichi Sankyo is applying this DXd ADC technology to various targeted antibodies and advancing clinical trials. In my presentation, I will introduce the unique features of the technology and present the latest nonclinical and clinical data.

Glucocorticoids (GCs) are potent anti-inflammatory drugs, but their widespread use is limited by systemic side effects. To address this, we have developed Glucocorticoid Receptor Modulator (GRM) Antibody-Drug Conjugates (ADCs) for inflammatory diseases. By precisely targeting the drug, ADCs aim to minimize systemic exposure and reduce adverse effects, while maximizing therapeutic efficacy. This innovative approach holds significant promise for treating a variety of inflammatory conditions, including autoimmune diseases and allergic disorders.

We have designed a novel siRNA containing gemcitabine in its backbone. This has demonstrated potent activity in preclinical models of pancreatic cancer, NSCLC and TNBC. This talk will demonstrate the synthesis and activity when conjugated to cetuximab for delivery to tumors in vivo.

FORCE is a modular platform which enables delivery of chemically diverse therapeutic payloads with widespread distribution to muscle and CNS. The FORCE platform is translating into the clinic with the ACHIEVE and DELIVER trials for DM1 and DMD, respectively. These encouraging clinical data and strong preclinical efficacy in FSHD and Pompe disease models support the potential of FORCE to address neuromuscular disorders with high unmet medical needs.

Here we present a method for tuning effector function inspired by antibody-drug conjugates. This methodology uses conjugation of polyethylene glycol (PEG) to native cysteines of an antibody to impair FcgR binding. Attenuated effector function can be permanent or restored through a de-conjugation process. Impacts of reversible PEGylation were assessed and applied to an agonist CD40 antibody. The PEGylated constructs displayed significant reductions in systemic cytokine production  in vivo, while retaining efficacy.

Over 90% of clinical ADCs use pan-cytotoxic payloads, but there is emerging interest in selectively-targeted payloads such as protein inhibitors and degraders. However, designing ADCs with non-traditional payloads is even more complex than cytotoxic ADCs, and challenging to optimize empirically. The proposed talk will highlight some new guiding principles for designing non-traditional ADCs, guided by vignettes of integrated lab-to-model workflows powered by Quantitative Systems Pharmacology.

The recent renaissance of ADCs was enabled by the dramatic increase in their therapeutic indexes, which can be achieved in two ways: either by making ADCs safer outside the tumors, resulting in an increased maximum tolerated dose—or inside the tumor, by improving their potency or reducing resistance formation. I will discuss several examples of how we achieved this goal with our next-generation Topo1 ADC platform.

Engineering antibody-drug conjugate linker stability significantly impacts payload disposition and thus affects both toxicity and anti-tumor activity. While improving ADC stability may result in better preclinical tolerability, the same advantage is not clear in the clinic. Nevertheless, engineering linker stability is a focus of considerable current attention. Data from clinical trials of antibody-drug conjugates suggest that more stable linkers impact the tolerability of ADCs in both expected and unexpected ways.

This presentation aims to 1) highlight stable bioconjugation approaches for increased ADC stability in vitro and in vivo, 2) describe tumor-selective linker designs that are aimed to improve the therapeutic index of ADCs by altering the toxicity profile and increasing tolerability, and 3) introduce ProAlk as a novel ADC payload with a differentiated mechanism of action and provide preclinical proof-of-concept studies.

• Auristatin glycoside ADCs with stabilized glycopeptide linker provide exceptionally wide therapeutic window and improved potency. Preclinical validation of CD33, TYRP-1, and HER2 targeting MMAU ADCs.
• Next-generation auristatin ADCs were developed based on MMAU (glucuronylated prodrug of MMAE) enabling both DAR=4 and DAR=8 ADCs with high potency.
• The novel mavg-MMAU linker-payloads enabled simultaneous improvements in both in vivo efficacy and tolerability; bystander efficacy and resistance to MDR drug efflux; and improved PK and lower off-target toxicity compared to vedotin ADCs.
• The improved linker was further applied to novel exatecan linker-payloads.