ADC Target Proteins: From HER2 to the Next-Generation Antigen Iteration
Antibody–drug conjugates (ADCs) have moved from the curiosity shelf to the front line of oncology in barely a decade, and the 2025 treatment calendar in the United States is already crowded with new data sets, new INDs and a new lexicon that reaches well beyond the familiar four-letter acronym "HER2." What follows is a single-resource tour of where the field stands, why it got there, and where it is heading next—written for translational scientists, investment analysts and clinicians who need more narrative than bullet points.
From the old guard to the next wave: how "classic" ADC targets still set the rules
When trastuzumab emtansine (Kadcyla) was approved in 2013 the community learned three enduring lessons: (i) the antigen must be abundant enough to sink 3–4 logs of cytotoxic payload into a cell, (ii) the internalization rate must outrun the systemic clearance rate, and (iii) the linker must stay put in circulation but fall apart the moment it hits the lysosome. HER2, CD30, CD33 and CD22 satisfied those axioms first, and they still shape every due-diligence checklist today. HER2 remains the single most validated ADC target across breast, gastric and non-small-cell lung cancer, with Enhertu (trastuzumab deruxtecan) now recognized as the first therapy to show benefit in the HER2-ultra-low expression space, forcing pathologists to re-write scoring guidelines. CD30 and CD22, meanwhile, are textbooks on how to build a hematology franchise: brentuximab vedotin and inotuzumab ozogamicin proved that microtubule inhibitors (MMAE) and calicheamicin payloads can each own a billion-dollar niche if the disease is sufficiently chemo-sensitive. Even CD33, the "elderly AML" target once written off because of narrow therapeutic index, has been resurrected through gentler conditioning regimens and combination studies with FLT3 or BCL-2 inhibitors. In short, the classics are not fading; they are the reference standard against which every newcomer is measured.
Related Proteins
Solid-tumor expansion: why Trop-2, Nectin-4, CLDN18.2 and B7-H3 suddenly feel inevitable
Once the hematology proof-of-concept was secure, the obvious next quest was to cure chemo-refractory solid tumors without the alopecia, neuropathy and neutropenia that force patients off trial. Four antigens have vaulted from obscurity to late-phase registrational programs in under five years, each illustrating a different design trick.
Trop-2 is a calcium signal transducer expressed on >80 % of triple-negative breast cancers (TNBC). Sacituzumab govitecan (Trodelvy) showed that a moderately labile CL2A linker coupled to SN-38 can overcome the multi-drug-resistance pump MDR1; the confirmatory ASCENT-04 study reported a 5.8-month PFS advantage over physician-choice chemotherapy in the post-immunotherapy space, pushing oncologists to adopt Trop-2 IHC as a routine biomarker. The bigger revelation, however, is that the same payload-linker backbone works in hormone-refractory prostate cancer and even EGFR-mutant lung cancer, turning Trop-2 into a "pan-solid" franchise similar to HER2.
Nectin-4 taught the field about lineage plasticity. Initially thought to be urothelial-restricted, enfortumab vedotin produced a 12.3-month median OS in the EV-301 trial and is now moving into neoadjuvian bladder cancer. Because Nectin-4 is transcriptionally induced by androgen-receptor blockade, Seattle Genetics and Astellas are testing an "EV + PARP + ARSI" triplet that could convert mCRPC from chronic disease to curative intent.
Claudin-18.2 is the first example of a tight-junction protein becoming druggable once tumors lose epithelial polarity. With 50–70 % of gastric and ~30 % of pancreatic lesions expressing the splice variant, Claudin-18.2 is essentially "HER2 for the upper GI tract." IMAB362 (zolbetuximab) showed that even a naked antibody can add 3 months of survival; add a cleavable Val-Cit linker plus MMAE and the ORR jumps to 60 % in the first-line setting. Both Astellas and Amgen have since paid >$500 M upfront to secure Japanese and global rights, respectively, signaling that Big Pharma expects front-line approval by 2027.
Finally, B7-H3 is emerging as the safety valve for tumors that learned to cloak themselves from PD-1 inhibition. Because B7-H3 expression is negligible in normal visceral organs but sky-high in small-cell lung cancer, pediatric neuroblastoma and castration-resistant prostate cancer, developers can push the payload dose without hitting gut or liver toxicity. The leading candidate, DS-7300 (a DXd-format ADC), achieved a 46 % objective response in heavily pre-treated SCLC at ASCO 2025, prompting FDA to grant orphan-drug designation and fast-track status simultaneously.
Related Proteins
Anatomy lesson: antibody, linker and payload—why the third generation is all about conditional release
First-generation ADCs (Kadcyla, Besponsa) used stable thioether linkers and non-cleavable chemistry; second-generation ADCs (Adcetris, Polivy) introduced cathepsin-cleavable dipeptides and maleimide-cap technology; third-generation products are now mixing pH, redox and enzyme triggers to create "conditional warheads" that explode only in the tumor micro-environment.
Take the DXd platform popularized by Daiichi Sankyo: a tetra-peptide (Gly-Gly-Phe-Gly) linker that is cleaved by cathepsin B and L, releasing a membrane-permeable topoisomerase I inhibitor whose potency is ten-fold higher than SN-38 and whose half-life is long enough to kill neighboring antigen-negative cells (the so-called bystander effect). Because the drug-antibody ratio (DAR) is pushed to 7–8 without triggering aggregation, DXd ADCs deliver roughly 20-fold more payload per cell than Kadcyla, explaining why responses are seen even when only 10 % of the tumor bulk stains HER2-positive.
Meanwhile, Pfizer's novel seco-DUBA linker uses a self-immolative para-aminobenzyl carbamate spacer that fragments at pH < 6.5, allowing release of the auristatin derivative in the acidic extracellular milieu of hypoxic tumors. Early cynomolgus data show a seven-day plasma half-life for the conjugate but <30 min half-life for the free toxin, dramatically widening the therapeutic index.
And let us not forget the re-emergence of DNA-crosslinkers: pyrrolobenzodiazepine (PBD) dimers such as tesirine and talirine are being paired with tumor-selective protease linkers to overcome MMAE resistance. The key safety tweak is a sulphoxide "safety-catch" that is reduced to the active sulphide only inside cells with high glutathione flux, sparing normal hepatocytes.
When magic bullets miss: resistance pathways and the combination playbook
ADC resistance mirrors the classical oncology escape routes—antigen loss, payload efflux, lysosomal trafficking defects and downstream mutations—but with kinetics compressed into months rather than years. The most elegant counter-strategy is orthogonal payload pairing. For example, HER2-low tumors that progress on Enhertu retain HER2 expression but up-regulate MDR1 and ABCC1; switching to a non-cross-resistant topoisomase II inhibitor (e.g., exatecan) or to a DNA-PK inhibitor payload restores cytotoxicity without re-engineering the antibody.
A second layer is to co-administer an agent that normalizes lysosomal acidification. Hydroxychloroquine or the vacuolar ATPase inhibitor bafilomycin can increase cathepsin activity, boosting linker cleavage and shifting the IC50 leftward two-fold in patient-derived xenografts.
Perhaps the most translatable approach, however, is to marry ADCs with immune checkpoint blockade. The payload-induced immunogenic cell death releases HMGB1 and calreticulin, converting a cold tumor hot. Early-phase data from the Tulip-005 basket trial show that sacituzumab govitecan plus pembrolizumab yields a 71% ORR in PD-L1-negative TNBC, essentially doubling the historical response rate of either agent alone. Similar chemo-immuno synergy is being explored with enfortumab vedotin plus nivolumab in muscle-invasive bladder cancer, and with DS-7300 plus dostarlimab in SCLC.
Clinical pipeline and M&A heat: why 2025 feels like a seller's market
By mid-2025 more than 340 ADCs worldwide have entered the clinic, but only ~15 % are sponsored by US-based companies, a statistic that keeps BD teams in Boston and South San Francisco awake at night. The scarcity premium is visible in upfront dollars: Merck paid $5.5 B for Daiichi's HER3-DXd ex-US rights, Gilead spent $2.1 B to acquire Forty-Seven just to access a CD47-ADC platform, and most recently Eli Lilly wrote a $1.6 B check for Emergence's Claudin-18.2 program still in Phase I.
Chinese innovators, flush with pre-clinical assets but lacking commercial reach in the West, have flipped the traditional risk curve. Companies like Kelun-Biotech, Innovent and CSPC are offering Phase II-ready molecules with differentiated linkers in exchange for co-development and co-marketing rights, a model that mirrors the 2005–2010 biotech partnering wave that brought us Velcade and Revlimid. The result is a virtuous circle: US pharma gains rapid access to best-in-class payloads, while Asian biotechs amortise R&D costs across global markets.
Investors should watch three catalyst clusters through 2026: (i) registrational read-outs for B7-H3 and Nectin-4 ADCs in SCLC and prostate cancer, respectively; (ii) first pivotal data on dual-payload constructs (cMET/EGFR and HER2/HER3) that could reset pricing benchmarks to $500 k+ per course; and (iii) FDA acceptance of the first AI-designed ADC, likely from AbCellera or Generate Biomedicines, which would validate in-silico optimisation and shorten discovery timelines to <12 months.
Take-home calendar: key US milestones to bookmark
- Q1 2026: ODAC review for DS-7300 in third-line SCLC (PDUFA date March 18)
- ASCO 2026: Phase III data for sac-TMT plus pembrolizumab in first-line TNBC (oral plenary expected)
- AACR 2026: First disclosure of Pfizer's dual-payload cMET-ADC in EGFR-exon20 lung cancer
- EHA 2026: Confirmatory OS for pivekimab sunirine (CD123 ADC) in BPDCN, the first potential approval in that ultra-orphan space
Bottom line
ADC science has matured from "let's bolt a toxin to an antibody" to a quantitative systems-engineering discipline where every amino acid in the linker, every log-fold in antigen density, and every nanomole of payload exposure is modelled, measured and monetized. HER2 opened the door; Trop-2, Nectin-4, Claudin-18.2 and B7-H3 are widening it; conditional-release linkers and dual-warhead payloads are about to kick the door off its hinges. For anyone covering oncology drug development, the next eighteen months will be less about incremental label expansions and more about category-defining approvals that could shift first-line standards across half a dozen solid tumors. Keep the resistance-biology playbook handy, but do not be surprised if the hottest ticket at ASCO 2026 is an ADC combination that finally makes chemotherapy obsolete.
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