The ADC landscape continuously evolves, but therapeutic index is still often only assessed in the clinic because it is challenging to systematically explore the impact of ADC design on organ-to-tumor distribution. Mechanistic computational modeling enables rapid evaluation of alternative ligand and payload designs for improved ADC behavior, such as better tumor penetration and reduced off-tumor toxicity. The proposed talk will provide advanced insights on the design-developability relationship for next-generation ADCs, using integrated lab-to-model workflows powered by QSP and PBPK models.

We present the case study featuring the design of a kidney-targeted siRNA–peptide conjugate optimized for selective tissue delivery, cellular uptake, and stable peptide–siRNA conjugation. Using AI-orchestrated multiparametric optimization, combining predictive AI models with physics-based methods, we identified peptide features that balance kidney tropism, uptake, and conjugation requirements. This workflow enabled rational design of a targeted delivery construct.

We describe the development of a novel radioconjugate modality built on de novo miniproteins designed using generative AI. These compact scaffolds enable precise targeting and efficient payload delivery. We outline the full pipeline, from computational design and optimization to experimental validation and in vivo evaluation. Our findings demonstrate the promise of AI-enabled miniproteins as a flexible platform for creating next-generation targeted radiotherapeutics.

The FORCE platform leverages Transferrin Receptor 1 (TfR1) to enable delivery of oligonucleotides and enzymes to muscle and the CNS. Preclinical data in models of DM1 and DMD demonstrate that the FORCE platform delivers broad functional improvement by addressing muscle and CNS manifestations of neuromuscular diseases. These results provide a strong rationale to apply TfR1-mediated delivery for neurological disorders.

Using the hyperstable Nanofitin protein scaffold, we have engineered multifunctional vectors with selective receptor targeting and half-life extension. One-step, direct conjugation of siRNAs with Nanofitins enable (1) receptor-mediated transcytosis through the blood-brain barrier and (2) efficient knock-down of intracellular targets in the brain. We will show in vivo demonstration of the Nanofitin-based shuttle approach to deliver oligos of therapeutic interest.

This presentation will explore the transformative impact of advanced bioconjugation technologies on ADC development. We’ll trace the move from traditional stochastic approaches to site-specific conjugation, highlighting gains in ADC homogeneity, stability, biophysical properties, and therapeutic index, featuring an AZ molecule as a case study. We’ll also address how conjugation methods influence manufacturability and review the latest conjugation chemistries to improve ADC efficacy, outlining directions for next-generation ADCs.

Peptide drugs degrade rapidly after intravenous administration, limiting efficacy. A new strategy covalently attaches peptides to endogenous circulating IgGs, extending their half-life without using engineered antibodies. This approach reduces immunogenicity and cost. Proof of concept with GLP-1 showed selective IgG modification and sustained therapeutic effect in vivo. This antibody-selective conjugation method may enable longer-acting treatments for various diseases.

We discuss using a physiological thiol gradient for designing a novel cleavable linker. The first non-disulfide-based linker that exploits the cellular thiol gradient as a trigger for selective intracellular drug release in the context of ADCs generated from an anti-human folate receptor alpha antibody, is discussed. Additionally, favorable stability in human serum and preliminary experimental data to support the proposed drug release mechanism from the drug-linker adduct would be presented.

Targeting non-internalizing tumor antigens presents unique challenges for antibody–drug conjugates (ADCs), as effective payload delivery cannot rely on cellular uptake. This presentation highlights general strategies explored in programs such as TAG72-targeted approaches, including linker design, extracellular payload release, and tumor microenvironment considerations. Emphasis is placed on balancing stability, specificity, and efficacy, underscoring broader insights into expanding ADC applications beyond internalizing targets.

AbTx develops next-gen ADCs using our TheranoStick platform, generating smaller formats (FDCs) for improved tumor access, faster clearance, and enhanced cytotoxicity. Our enzymatic conjugation (transglutaminase + patented Q-Tag system) ensures site-specific payload attachment across full-length antibodies, Fabs, scFvs, and VHHs, boosting efficacy and safety.

Bispecific ADCs can improve payload delivery through enhanced tumor targeting, increasing efficacy and safety in heterogeneous cancers. However, identifying synergistic target pairs remains challenging due to combinatorial complexity. Valink’s high-throughput universal assembly platform enables rapid generation and screening of thousands of bispecific ADCs to uncover optimal target combinations. Using this approach, Valink is advancing a colorectal cancer program showing strong synergy over monospecific ADCs with promising in vivo activity.

VelaVigo has developed robust proprietary target discovery and multispecific antibody technology platforms to deliver first-in-class (FIC) bispecific ADC programs. The representative programs will be showcased in the presentation, with preclinical data demonstrating superior efficacy compared to monospecific ADCs in various target expression settings. The programs also show favorable tox profiles and excellent developability making them strong candidates for further clinical development.

Antibody-drug conjugates have validated tumor-targeted payload delivery but size limitations constrain their tolerability and efficacy. K2B Therapeutics is developing engineered SIRPa protein drug conjugates (PDCs) that exploit CD47, a universally overexpressed tumor antigen with a unique resistance profile, for selective cytotoxic payload delivery. As a smaller tumor targeting moiety, the SIRPa scaffold is cleared rapidly from systemic circulation and is poised to achieve deep tumor penetration unlike large-format conjugates. Preclinical studies across multiple solid tumor models demonstrate complete tumor regression across a wide efficacious dose range, with a tolerability profile that supports clinical advancement into indications where ADCs may have underdelivered.

Proteolysis-targeted chimeras (PROTACs) show therapeutic promise, yet poor oral bioavailability and lack of cell-type specificity remain key challenges. Antibody-targeted delivery via Degrader-ADCs can address these limitations, though their generation is challenging. We introduce PROxAb Shuttles: a plug-and-play platform utilizing camelid-derived VHH domains engineered into bispecific antibody scaffolds. These non-covalent antibody-PROTAC complexes prolong half-life from hours to days, enabling in vivo anti-tumor efficacy, sustained target protein degradation, and expedited Degrader-ADC discovery.

Antibody–drug conjugates (ADCs) and peptide–drug conjugates (PDCs) share modular architectures of targeting ligand, linker, and payload but differ fundamentally in size, pharmacokinetics, tumor penetration, manufacturability, and immunogenicity. ADCs provide prolonged circulation and validated clinical efficacy, whereas PDCs enable deeper tissue diffusion, flexible chemistry, and reduced immunogenicity. Understanding these complementary design principles, including linker stability, targeting specificity, and payload selection, guides rational development of next-generation targeted therapeutics.

This presentation explores innovative technologies and development strategies advancing antibody-oligonucleotide conjugates (AOCs), a novel therapeutic class combining tissue-specific delivery with RNA-targeting precision. Key topics include technical and development approaches that collectively inform AOC design, enhance therapeutic potential, and enable broader application across diverse disease areas.

Antibody–drug conjugates (ADCs) are complex therapies with unique immunogenicity risks. This presentation summarizes current ADC immunogenicity insights, discussing how factors like antibody format, conjugation chemistry, linker stability, payload, and impurities affect anti-drug antibody (ADA) formation. Clinical data on ADA incidence and impact will be reviewed, along with a streamlined de-risking framework for in silico and in vitro risk assessment and bioanalytical strategies.