While ADCs have shown clinical promise, their efficacy is often compromised by variable antigen expression within tumors. Compared to single-drug variants, our ADCs co-loaded with Lu177 and MMAE exhibited superior antitumor effects in xenograft tumor models with low or heterogeneous HER2/TROP2 expression, highlighting its advantage in overcoming heterogeneity-driven resistance. These advancements support our platform's potential to enable more effective and safer therapies for breast cancer and other treatment-resistant malignancies.

Antibody-drug conjugates (ADCs) have ascended to a leading position among therapeutic modalities for oncology indications. However, great opportunities exist to engineer improvements in ADC safety and efficacy. This presentation discusses pharmacokinetic strategies that are under current development for increasing ADC distribution within solid tumors, decreasing off-target exposure to ADC payloads, and enhancing the selectivity of ADC delivery to cancer cells. Special attention will be paid to the use of physiologically-based pharmacokinetic modeling to guide engineering of multi-specific ADCs for increased selectivity and efficacy.

We describe a novel engineered multivalent multispecific therapeutic approach (SYNTHBODY) that enables targeting of combinatorial “synthetic” cancer targets. The SYNTHBODY approach as an ADC leads to log order greater internalization and in vitro potency when compared with an approved benchmark or bispecific ADC approaches with its component binders. We highlight the streamlined discovery, layered logic-gated architecture, optimized developability, pharmacokinetics, and in vivo efficacy using an example SYNTHBODY.

The Araris’ site-specific, one-step linker conjugation technology aims at generating stable, safe and highly potent ADCs without the need for antibody engineering. We present a novel Nectin-4 targeting triple-warhead ADC using a combination of MMAE and two different topoisomerase-1 inhibitors designed to treat a broad range of solid tumors, and demonstrate that a combination of multiple payloads in one ADC can lead to synergistic effects in mouse models while still being well tolerable.

CatenaBio has developed highly stable, dual-payload ADC combination therapies, with tunable payload ratios. Our selective Multi-Payload Conjugate (MPC) conjugation platform allows the attachment of distinct payloads targeting different mechanisms of action at three unique sites on antibody scaffolds, replacing the unstable maleimide bond with a more stable C-Y bond. MPCs, targeted combination chemotherapies within a single molecule, deliver superior efficacy with reduced toxicities to address shortcomings in current ADCs.

Aiming to innovate beyond the traditional ADC approach to develop medicines with safer and more durable therapeutic profile, we established a next-generation ADC technology with novel oligonucleotide payloads, extending the therapeutic mechanism beyond cytotoxic agents. The presentation will highlight Tallac’s novel Toll-like Receptor Agonist Antibody Conjugate (TRAAC) platform which employs a novel immune modulating oligonucleotide payload. Preclinical to clinical translation is demonstrated by a case study of TAC-001, a toll-like receptor 9 agonist ADC designed for targeted immune activation for the treatment of cancer. 

Antisense-oligonucleotides are a promising drug modality for the treatment of neurological disorders, but their administration via intrathecal delivery is limiting the broader clinical application of ASOs. Our team’s research focuses on conjugating the ASO to a  Brainshuttle antibody that facilitates access to the central nervous system (CNS) via transcytosis at the blood–brain barrier. Our first results in wt mice suggest a broad biodistribution across brain regions. Promising in vitro activity and in vivo pharmacokinetic behavior of optimized Brainshuttle-ASO conjugates suggest that such designs have the potential to serve as a blueprint for peripherally delivered ASO-based drugs for the CNS.

Lytica Therapeutics has developed a novel Stapled Internalization Promoter (SIP) platform that fundamentally enhances how ADCs access and kill tumor cells. SIPs are hydrocarbon-stapled peptides conjugated to antibody scaffolds that actively drive receptor-mediated endocytosis of ADC-target complexes, independent of intrinsic receptor trafficking kinetics. By increasing the rate and magnitude of intracellular payload delivery, SIP-enabled ADCs achieve potent antitumor activity at substantially lower doses, shifting the efficacy and toxicity curves apart. Preclinical data demonstrating a superior therapeutic window compared to current state-of-the-art ADCs suggest that SIP technology has the potential to serve as a modular platform for next-generation ADCs with meaningfully improved tolerability across targets and tumor types.

• JSKN033: A high-concentration, subcutaneous co-formulation of a PD-L1 inhibitor (envafolimab) and a HER2 biparatopic ADC. Shows improved safety & promising efficacy in late-line cervical cancer. A Phase II trial in lung cancer is ongoing.
• JSKN022: A novel "2-in-1" bispecific ADC targeting PD-L1 and ITGB6. Currently in Phase I expansion, it has demonstrated strong antitumor activity and good tolerance.
• JSKN027: A tetravalent bispecific ADC targeting PD-L1 and VEGFR2. Currently in dose escalation, showing strong activity and good tolerance.Initial clinical data for 022 and 027in solid tumors are expected later this year.
  

Bispecific ADCs represent cutting-edge advancement whose design involves the intelligent choice of target antigens, antibody formats, linker, payload, and conjugation technology. We report on this dual-targeting strategy's potential to target a wider range of tumors, overcome drug resistance, increase internalization rates and cell killing, and improve the safety profile by increasing selectivity and reducing off-tumor toxicity

Two programs are showcased in this presentation. One is an FIC-bispecific ADC targeting both CD79b and CD20, with preclinical data demonstrating superior efficacy compared to Polatuzumab Vedotin (PV) in both PV sensitive and resistant models, and excellent tumor inhibition in PDX model of Richter's syndrome. The other is an FIC bispecific anti-CDH17/CLDN18.2 ADC therapy, potentially addressing the limitation of targeting CLDN18.2 or CDH17 alone. Both programs also show favorable PK and tox profiles in rat and cyno, and excellent developability, making it a strong candidate for further CMC development.

Sutro’s XpressCF+ cell-free protein synthesis platform enables site-selective dual-payload ADCs with defined DARs. STRO-227, a PTK7-targeting ADC combining exatecan and MMAE, demonstrates superior anti-tumor activity, overcomes resistance, and shows favorable tolerability versus single-payload ADCs. The platform is further applied to Topo1i × PARPi combinations to enhance efficacy and expand therapeutic potential.

Herein, we introduce a new antibody-drug conjugate class (HiDARs) featuring polymer scaffolds that carry 50–200 kinase inhibitor payloads via cleavable linkers. Anti-HER2 conjugates incorporating PI3K/mTOR inhibitors exhibit potent activity in breast cancer tumor cells and demonstrate in vivo efficacy in mouse models. This platform broadens ADC payload diversity, enhancing safety and expanding applications beyond conventional cytotoxic payloads.

Antibody–drug conjugates (ADCs) have revolutionized cancer therapy but face limits in payload diversity and drug-to-antibody ratios (DARs). I will present antibody–bottlebrush conjugates (ABCs), which integrate antibodies with polymeric prodrugs to achieve ultra-high DARs without compromising antibody function. This architecture enables safe delivery of diverse payloads, yielding superior efficacy and reduced toxicity in tumor models.