Antibody-drug conjugates (ADC) have become a defining force in precision oncology. Traditional ADCs combine monoclonal antibodies targeting tumor-associated antigens with highly potent cytotoxic payloads, most commonly tubulin inhibitors or topoisomerase I inhibitors. Over the past decade, this model has delivered meaningful clinical benefit and multiple regulatory approvals.[1][2]
Yet as ADCs continue to mature, their limitations are increasingly clear. Their therapeutic index generally remains narrow, drug resistance remains an issue, and high drug-to-antibody ratios (DARs) are often required to achieve sufficient efficacy. The question is no longer whether ADCs work. It is whether repeating the same format will meaningfully expand what they can achieve.[3]
The shift becomes visible when looking at the numbers. The Beacon database currently tracks 2,334 ADC assets globally. In 2025, traditional ADC programs grew by 27% year-on-year (YoY), whilst novel ADC formats grew by 72% over the same period. Roughly a quarter of all ADCs in development are now classified as novel formats. The most rapid expansion is occurring in bispecific ADCs, antibody oligonucleotide conjugates, and dual payload designs, but it also includes degrader antibody conjugates and smaller targeting formats such as peptides and fragments.[4][5][6][7]
Conversations at World ADC London this week echoed what these numbers suggest. The field is entering a more biologically driven phase. ADCs as a modality are no longer in question. Instead, differentiation is shifting toward how convincingly a bioconjugate solves delivery, resistance, and tolerability constraints that first-generation designs have struggled to overcome.[8][9]
Bispecific ADCs illustrate this shift. The number of disclosed bispecific ADC programs increased by 65% YoY in 2025. Interestingly, despite the theoretical breadth of possible target combinations, much of the current bispecific landscape remains concentrated around a relatively small set of familiar targets. A key consideration for developers is enforcing ‘function over format’ via target pair selection and functional rationale. The conversation has moved beyond whether a construct binds two antigens.
The real question is whether that pairing meaningfully alters tumor biology, internalisation, resistance pathways, or therapeutic index compared with a monospecific ADC.
Payload strategy
Payload strategy is undergoing a similar evolution. Topoisomerase I inhibitors and tubulin inhibitors still dominate clinical pipelines. However, saturation of this payload space and increasing awareness of resistance mechanisms are pushing developers to explore alternative approaches.
Multiple speakers at World ADC London emphasised that potency alone is no longer the differentiator. Safety is emerging as the true ceiling. Patients discontinue treatment due to tolerability limits, not because cytotoxic payloads are insufficiently potent. The focus is shifting toward widening the therapeutic index, reducing systemic exposure, and enabling longer duration therapy without cumulative toxicity.
Dual-payload ADCs
Dual-payload ADCs are moving from a theoretical concept to clinical reality. The first wave entered the clinic in 2025, and early readouts will be closely watched. Importantly, discussions around dual payload design were framed less as novelty and more as resistance management.
Some experts drew parallels to combination chemotherapy and antiviral regimens, in which multi-mechanism approaches reduce the likelihood of tumour escape. The ambition is not merely to increase cytotoxicity, but to limit the evolutionary paths available to the tumour. [9][10]
Degrader antibody conjugates
Degrader antibody conjugates represent another area of interest. There remain 38 degrader antibody conjugates in active preclinical development. After rapid expansion in 2024, the field experienced setbacks in 2025 with two clinical discontinuations. However, this has sharpened rather than dampened enthusiasm. In discussions with developers, degrader conjugates are viewed as a format that must ‘justify itself’ through a clear functional advantage.
They are being positioned for settings where targeted protein degradation can achieve outcomes that cytotoxic payloads or small molecule degraders alone cannot. At the same time, uncertainties remain around intracellular delivery efficiency and translational predictability.
Antibody oligonucleotide conjugates
Antibody oligonucleotide conjugates are also accelerating rapidly, with YoY growth exceeding 100%. Several programs have received expedited regulatory designations, positioning them for potential approval as early as 2026.
What is notable from conversations with developers is that enthusiasm is strongest outside oncology. In neuromuscular and rare genetic diseases, AOCs are being viewed less as an extension of ADC technology and more as a precision delivery solution.
Peptide, fragment, and other small-format conjugates
Peptide, fragment, and other small-format conjugates are re-emerging, sometimes described as a fast in, fast out strategy. The appeal lies in improved tumor penetration, faster systemic clearance, and compatibility with certain non-cytotoxic payload classes. These formats are attracting particular interest in tumors where antibody size may limit effective delivery. However, kidney exposure, pharmacokinetic control, and limited clinical precedent remain significant hurdles. There is a strong appetite for translational data that moves beyond theoretical advantages to demonstrate measurable improvements in tissue distribution and safety.[11][12]
One statistic that was discussed repeatedly at World ADC London was that approximately 1% of an administered ADC dose reaches the tumor. Much of the innovation across novel conjugates can be interpreted as an attempt to either increase that fraction or make that 1% more effective. Whether through better internalisation, improved linker stability, alternative payload mechanisms, or more selective targeting, the objective is the same. Deliver more of the right biology to the right cells, with less collateral damage.
Taken together, these trends suggest that the centre of gravity in ADC innovation has shifted, and developing a novel ADC format is being viewed as almost less risky than the risk of not innovating in this highly competitive space. Novel conjugates are not being judged solely on structural complexity. They are being judged on whether they meaningfully expand the therapeutic window, overcome resistance, and address delivery constraints that have defined the limits of first-generation ADCs.
If traditional ADCs proved that targeted cytotoxic delivery can work, the next generation is attempting to prove that it can work better, smarter, and in diseases where cytotoxicity was never the right answer to begin with.
Taken together, these trends suggest that the centre of gravity in ADC innovation has shifted. In many cases, developing a novel ADC format is now perceived as less risky than failing to differentiate in an increasingly saturated and competitive landscape. The greater risk may no longer be technical novelty, but strategic stagnation.
Biology as a true differentiator
Novel conjugates are not being judged solely on structural complexity. They are being evaluated on whether they can meaningfully expand the therapeutic window, overcome resistance, and address the delivery constraints that have defined the limits of first-generation ADCs. Biology, not format, is becoming the true differentiator.
If traditional ADCs have proven that targeted cytotoxic delivery can work, the next generation seeks incremental improvements to expand its impact.
These trends directly shaped the focus of the Novel Conjugates Summit 2026 (March 17-19, 2026, Boston, MA), which is designed around the practical questions teams are now asking as the field advances. Join this upcoming event to meet drug developers who are discussing how next-generation conjugates are being designed, evaluated, and differentiated as novel ADCs move into a more competitive, data-driven phase.
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Reference
[1] Niegisch G, Zschäbitz S, Eckstein M, Klümper N. Von ungezielt zu Präzisionsonkologie: Prädiktive Biomarker und Target-Therapien beim fortgeschrittenen Urothelkarzinom [From nontargeted to precision oncology: predictive biomarkers and targeted therapies in advanced urothelial carcinoma]. Urologie. 2026 Jan 28. German. doi: 10.1007/s00120-026-02765-z. Epub ahead of print. PMID: 41603912.
[2] Ciliberti EA, Calleja-Holgado FJ, Lheureux S, Van Gorp T, Colombo I, Madariaga A. Safety of antibody-drug conjugates in gynecologic cancers: current evidence and management approaches. Int J Gynecol Cancer. 2025 Nov;35(11):102117. doi: 10.1016/j.ijgc.2025.102117. Epub 2025 Aug 19. PMID: 40934857.
[3] Wang R, Hu B, Pan Z, Mo C, Zhao X, Liu G, Hou P, Cui Q, Xu Z, Wang W, Yu Z, Zhao L, He M, Wang Y, Fu C, Wei M, Yu L. Antibody-Drug Conjugates (ADCs): current and future biopharmaceuticals. J Hematol Oncol. 2025 Apr 30;18(1):51. doi: 10.1186/s13045-025-01704-3. PMID: 40307936; PMCID: PMC12044742.
[4] Zhou X, Han Y, Fang Y, Ma P, Zhou J, Jiang Y, Xing S, Tang Q, Hou Y, Wang S, Li N. Antibody-drug conjugates: Current challenges and innovative solutions for precision cancer therapy. Med. 2025 Oct 10;6(10):100849. doi: 10.1016/j.medj.2025.100849. Epub 2025 Sep 30. PMID: 41033317.
[5] Tao J, Gu Y, Zhou W, Wang Y. Dual-payload antibody-drug conjugates: Taking a dual shot. Eur J Med Chem. 2025 Jan 5;281:116995. doi: 10.1016/j.ejmech.2024.116995. Epub 2024 Oct 23. PMID: 39481229.
[6] Jin S, Sun Y, Liang X, Gu X, Ning J, Xu Y, Chen S, Pan L. Emerging new therapeutic antibody derivatives for cancer treatment. Signal Transduct Target Ther. 2022 Feb 7;7(1):39. doi: 10.1038/s41392-021-00868-x. PMID: 35132063; PMCID: PMC8821599.
[7] Fujii T, Matsuda Y. Novel formats of antibody conjugates: recent advances in payload diversity, conjugation, and linker chemistry. Expert Opin Biol Ther. 2023 Jul-Dec;23(11):1053-1065. doi: 10.1080/14712598.2023.2276873. Epub 2023 Dec 15. PMID: 37953519.
[8] Guo H, Xie H, Huang Y, Jia J, Kong X, Yang Q, Gai S, Li W, Bai L, Zhang L, Chen X, Ye Z, Ye H, Zhao L, Xu Y, Du Y, Zhang X, Chen M, Zhou X, Zhao RY. The development and evaluation of a tublysine-based antibody-drug conjugate with enhanced tumor therapeutic efficacy. Front Pharmacol. 2025 Feb 10;16:1532104. doi: 10.3389/fphar.2025.1532104. PMID: 39995411; PMCID: PMC11847841.
[9] Wen M, Yu A, Park Y, Calarese D, Gerber HP, Yin G. Homogeneous antibody-drug conjugates with dual payloads: potential, methods and considerations. MAbs. 2025 Dec;17(1):2498162. doi: 10.1080/19420862.2025.2498162. Epub 2025 May 5. PMID: 40322862; PMCID: PMC12054377.
[10] Long R, Zuo H, Tang G, Zhang C, Yue X, Yang J, Luo X, Deng Y, Qiu J, Li J, Zuo J. Antibody-drug conjugates in cancer therapy: applications and future advances. Front Immunol. 2025 May 21;16:1516419. doi: 10.3389/fimmu.2025.1516419. PMID: 40469310; PMCID: PMC12133739.
[11] Deonarain MP, Yahioglu G, Stamati I, Pomowski A, Clarke J, Edwards BM, Diez-Posada S, Stewart AC. Small-Format Drug Conjugates: A Viable Alternative to ADCs for Solid Tumours? Antibodies (Basel). 2018 Mar 31;7(2):16. doi: 10.3390/antib7020016. PMID: 31544868; PMCID: PMC6698822.
[12] Deonarain MP, Yahioglu G. Current strategies for the discovery and bioconjugation of smaller, targetable drug conjugates tailored for solid tumor therapy. Expert Opin Drug Discov. 2021 Jun;16(6):613-624. doi: 10.1080/17460441.2021.1858050. Epub 2021 Jan 11. PMID: 33275475.
Featured image: 16th World ADC 2026, London, UK. Image courtesy © 2026 Kate Woodfort/Hanson Wade. Used with permission.
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