Beyond Topo I: Why Genentech’s $1B Deal with DualityBio Signals the Next Phase of ADC Development

Over the last five years, almost every antibody-drug conjugate (ADC) that transformed clinical oncology has relied on the exact same mechanism to kill cancer cells. From Enhertu (delivering DXd) to Trodelvy (delivering SN-38), the industry aggressively diversified its targets but standardized heavily on one warhead chemistry: camptothecin-class topoisomerase I (Topo I) inhibitors. The field is now paying the price for that standardization: predictable, cross-molecule payload resistance.

Figure 1. Structure of topoisomerase I inhibitors-based ADCs ^[1].

On August 28, 2026, Genentech made a decisive $1 billion move to get ahead of this resistance curve. Their global collaboration with DualityBio is built around DUPAC (DualityBio Unique Payload Antibody Conjugate), a platform dedicated to novel-mechanism payloads ^[3]. DualityBio leads discovery and early clinical development through Phase 1a, after which Genentech takes an exclusive worldwide license and sole responsibility for development and commercialization.

Genentech is not short of antibodies, targets, or ADC expertise. What they just licensed is warhead diversity.

Why topoisomerase I inhibitors dominate today's ADCs

DXd and SN-38 are both camptothecin derivatives that trap TOP1-DNA cleavage complexes and convert them into replication-associated double-strand breaks. Paired with cleavable linkers, high drug-to-antibody ratios, and payloads permeable enough to kill neighboring antigen-negative cells, that chemistry delivered the response rates that pulled ADCs out of late-line salvage and into earlier treatment ^[4].

Success bred concentration, and concentration has a consequence that only surfaces now that these drugs are moving into second and first line. A patient can receive three ADCs in sequence, against three different antigens, and see essentially one cytotoxic mechanism throughout. That matters only if payload resistance is real and portable between molecules. The data increasingly say it is both.

Figure 2. Schematic illustration of the therapeutic mechanism of TOP1-ADC ^[4].

What is ADC payload resistance, and why does it travel between ADCs?

The clinical hint arrived early. When a Massachusetts General Hospital team sequenced metastases from a patient with triple-negative breast cancer who had responded deeply to sacituzumab govitecan and then progressed, they found two escape routes running in parallel in different lesions: a novel TROP2 mutation, T256R, that cut antibody binding by more than 80%, and TOP1 E418K, the canonical mutation that blunts topoisomerase I inhibitors ^[5]. The tumor could exit through the antibody or through the warhead.

Work published in Clinical Cancer Research in 2026 takes the second route apart. Investigators generated breast cancer lines resistant to trastuzumab deruxtecan and to sacituzumab govitecan, then asked what had actually changed. Antigen expression held. Internalization held ^[6]. Resistance in both models was payload-specific, driven by upregulation of ATP-binding cassette efflux transporters that pump the released cytotoxic out of the cell before it can do enough damage.

Figure 3. Payload-derived resistance in Topo1-inhibitor ADC ^[6].

Because efflux machinery recognizes the payload rather than the antibody, resistance moves with the warhead. T-DXd-resistant models showed reduced sensitivity to SN-38 despite never having seen it. Related work in urothelial carcinoma implicates ABCG2-mediated SN-38 efflux in sacituzumab govitecan resistance, and a broader survey has now catalogued which ADC payloads are ABCG2 and ABCB1 substrates ^[7].

The corollary is actionable. When the same group switched to a mechanistically distinct payload, an MMAF conjugate, antitumor activity was restored in cell-based assays and in xenografts. Their conclusion: non-cross-resistant payload classes should guide ADC sequencing, and payload diversification is a clinical strategy rather than a preclinical curiosity.

Which reframes how we describe a patient. "Post-Enhertu" and "post-Trodelvy" are administrative labels. Biologically, that patient may simply be post-Topo I, and switching the antigen while keeping the chemistry may buy less than the trial design assumes.

Inside DualityBio's DUPAC platform: DUP5, DUP9, and DUP10

DualityBio built DUPAC around that gap. Rather than another optimized camptothecin, the platform pairs several mechanistically distinct payloads with linkers matched for plasma stability and tumor-specific release. Three payloads have been disclosed: DUP5, DUP9, and DUP10.

Figure 4. Next-generation antibody-drug conjugates (ADCs) built on the Company's proprietary DualityBio Unique Payload Antibody Conjugate (DUPAC) platform ^[8].

The selection criteria are informative. DualityBio screens for high potency, activity across tumor types, short systemic half-life so free drug clears quickly after release, and bystander activity strong enough to matter in heterogeneous solid tumors. Rapid clearance is the underappreciated one. It is what allows a potent non-Topo I warhead to widen the therapeutic index instead of relocating toxicity.

The stated goal is explicit: DUPAC is designed to retain antitumor activity in tumors that are resistant or less responsive to topoisomerase inhibitor-based ADCs. Conference data for DUP5-based conjugates have shown activity in tumor models relatively insensitive to Topo I payloads, with non-human primate tolerability ^[9].

Two caveats are worth stating plainly. Models that are intrinsically insensitive to Topo I payloads are not the same population as patients who progressed on trastuzumab deruxtecan, and no DUPAC conjugate has read out clinically. The $45 million upfront is small against the milestone total, which is a reasonable way to price scientific rationale that still needs a Phase 1.

How payload diversification changes ADC trial design and sequencing

If payload class is a resistance axis, four things follow for programs in design now.

Prior therapy needs to be captured at the level of mechanism, not brand: stratifying by "prior ADC" collapses a patient who received an MMAE conjugate and one who received two deruxtecan conjugates into the same bucket. Efflux transporter expression becomes a candidate enrichment biomarker rather than a mechanistic footnote. Dual-payload conjugates entering clinical development follow the same logic, since two distinct mechanisms are harder for a single efflux or target mutation to defeat. And microtubule inhibitors, largely written off after the first ADC generation, look different once the resistance question is reframed, because the payload was never the problem so much as the linker and DAR chemistry around it.

The payload can no longer be the last component chosen. It is a strategic decision made alongside the target.

Cyagen HUGO-Ab™: Engineered for combinatorial ADC discovery

None of this makes the antibody less important. A novel-mechanism warhead only helps if enough of it reaches the right cells, which puts more pressure on specificity, affinity tuned for tumor penetration rather than maximum binding, efficient internalization and lysosomal processing, and compatibility with the linker chemistry the payload requires. Antigen density and heterogeneity determine how much bystander effect a program can count on.

The practical question is combinatorial: which antibody, against which target, with which linker and which payload, remains effective given what the tumor has already survived. Answering it means generating enough antibody diversity to satisfy all four constraints at once rather than sequentially.

Cyagen's HUGO-Ab™ Fully Human Antibody Discovery Platform is built for that stage. It combines HUGO-Mab™ fully human monoclonal antibody mice, HUGO-Light™ common light-chain mice for bispecific and multispecific formats, and HUGO-Nano™ fully human single-domain antibody mice, with AI-enabled repertoire analysis through AbSeek™, functional screening, and in vivo validation in translational tumor models. For ADC programs, that means moving from target selection to internalization-competent, format-appropriate candidates with efficacy data in biologically relevant systems, rather than in isolation from the payload they will carry.

The defining question in ADC development has shifted from “Can we deliver a cytotoxic?” to “Will it work after the last one failed?” Cyagen provides the end-to-end infrastructure to ensure your next-generation ADC answers that question definitively.

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Reference

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[2] Tsuchikama K, Anami Y, Ha SYY, Yamazaki CM. Exploring the next generation of antibody-drug conjugates. Nat Rev Clin Oncol. 2024 Mar;21(3):203-223. doi: 10.1038/s41571-023-00850-2. Epub 2024 Jan 8. PMID: 38191923.

[3] DualityBio. DualityBio enters a global collaboration and license agreement with Genentech to develop next-generation ADCs built on DualityBio's DUPAC novel-payload platform. DualityBio. 2026 Aug 28. Available from: https://en.dualitybiologics.com/news/614.html

[4] Han S, Lim KS, Blackburn BJ, Yun J, Putnam CW, Bull DA, Won YW. The Potential of Topoisomerase Inhibitor-Based Antibody-Drug Conjugates. Pharmaceutics. 2022 Aug 16;14(8):1707. doi: 10.3390/pharmaceutics14081707. PMID: 36015333; PMCID: PMC9413092.

[5] Coates JT, Sun S, Leshchiner I, Thimmiah N, Martin EE, McLoughlin D, Danysh BP, Slowik K, Jacobs RA, Rhrissorrakrai K, Utro F, Levovitz C, Denault E, Walmsley CS, Kambadakone A, Stone JR, Isakoff SJ, Parida L, Juric D, Getz G, Bardia A, Ellisen LW. Parallel Genomic Alterations of Antigen and Payload Targets Mediate Polyclonal Acquired Clinical Resistance to Sacituzumab Govitecan in Triple-Negative Breast Cancer. Cancer Discov. 2021 Oct;11(10):2436-2445. doi: 10.1158/2159-8290.CD-21-0702. Epub 2021 Aug 17. PMID: 34404686; PMCID: PMC8495771.

[6] Rampa DR, Seo M, Ogata N, Yang Z, Sridhar N, Fujii T, Wannaphut C, Maynard JA, Tsuchikama K, Sledge GW Jr, Ueno NT, Lee J. Payload Diversification Overcomes Resistance and Guides Sequential Antibody-Drug Conjugate Therapy in Breast Cancer. Clin Cancer Res. 2026 Apr 15;32(8):1454-1461. doi: 10.1158/1078-0432.CCR-25-3321. PMID: 41591991; PMCID: PMC13055631.

[7] Prantl I, Grausenburger R, Müller J, Baumfried O, Ertl IE, Nössing C, Herek P, Pirker C, Valcanover D, Bastos-Moreira Y, Borsos E, Hauser LM, Rupp L, Lemberger U, Gabler-Pamer L, Laukhtina E, Suleja A, Oszwald A, Wasinger G, Compérat E, Marko D, Shariat SF, Berger W, Englinger B. ABCG2-mediated SN-38 efflux drives resistance to Sacituzumab govitecan in urothelial carcinoma. Cancer Lett. 2026 Mar 1;640:218254. doi: 10.1016/j.canlet.2026.218254. Epub 2026 Jan 13. PMID: 41539407.

[8] DualityBio. Duality Unique Payload Antibody Conjugate (DUPAC). Duality Biotherapeutics. Available from: https://en.dualitybiologics.com/17335756971071/2.html. Accessed September 3, 2026.

[9] Lin S, Li B, Zhang Y, Yao J, Liang L, Xu Y, Shi R, Zhu Z, Qiu Y, Hua H. DUP5, a novel mRNA translation inhibitor as a payload for antibody drug conjugates, exhibits promising preclinical efficacy. Mol Cancer Ther. 2025;24(10 Suppl):B129. doi:10.1158/1535-7163.TARG-25-B129.