Twice the punch: The emergence of dual-payload antibody and peptide drug conjugates

The emergence of dual-payload antibody-drug conjugates (ADCs) and peptide-drug conjugates (PDCs) could mark a significant evolution in targeted therapeutics. Unlike traditional single-payload designs, dual-payload systems enable the simultaneous delivery of two complementary cytotoxic agents or functional molecules within a single medicine. This strategy offers the potential to overcome drug resistance, enhance tumor selectivity, and broaden the therapeutic window by combining distinct mechanisms of action. By applying this approach to both antibody and peptide systems, researchers can harness the targeting power of biologics and the versatility of peptides to create next-generation conjugates that act with greater precision and effectiveness. 

In this article, we explore the emerging fields of dual-payload ADCs and dual-payload PDCs. 

Advantages of dual-payload ADCs and PDCs 

Dual-payload ADCs and PDCs both build on the principle of using a targeted carrier to deliver therapeutic payloads selectively to diseased cells. However, compared to traditional single-payload ADCs or PDCs, adding a second payload expands what these molecules can achieve, enabling multiple mechanisms of action within a single construct. Or, to put it more simply: these next-generation drugs act like combination therapies but are delivered in a single medicine.  

This strategy offers several advantages over traditional single-payload conjugates, including the ability to tackle heterogeneous tumours, enhance potency, and reduce the likelihood of resistance while maintaining targeted delivery. 

Looking more closely at ADCs, using dual payloads for these drugs are particularly valuable in addressing tumour heterogeneity and adaptive resistance – something that has traditionally been very difficult to overcome when treating cancer, especially solid tumors. While single-payload ADCs rely on one cytotoxic mechanism, which may leave resistant subpopulations unharmed, carrying two mechanistically distinct drugs means that dual-payload ADCs can kill diverse tumour cells simultaneously.  

Dual-payload PDCs, meanwhile, offer similar advantages to ADCs, but they have added flexibility from their small, modular scaffolds; in essence, they are tiny, customizable carriers that can be engineered to deliver one or more therapeutic payloads precisely where they are needed. Peptides also tend to penetrate tumours more efficiently than antibodies, and equipping them with two payloads allows simultaneous action on multiple cellular targets. Moreover, because peptides can be precisely designed, scientists can control how and when each drug is released. This means the two payloads can be activated one after the other, in specific parts of the tumour, or only under certain tumour-specific conditions. As a result, dual-payload PDCs can deliver powerful combination therapies safely and efficiently. 

Emerging therapies: Dual-payload ADCs and PDCs in development for cancer 

As emerging therapies, there are not yet many dual-payload drugs in clinical trials. Currently, ADCs are ahead of PDCs in terms of development stage, as there are two dual-payload ADCs in early-stage trials, whereas dual-payload PDCs have yet to enter the clinic. Below, we detail the most advanced ADC and PDC candidates to date.  

Dual-payload ADCs: Innovent’s IBI3020 and Chengdu Kanghong’s KH815 have entered the clinic  

When looking at the development pipeline for dual-payload ADCs, Innovent Biologics is currently ahead of the pack, as its drug candidate became the first dual-payload ADC to begin in-human studies when the first patient was dosed in a phase 1 trial in April.   

The candidate, called IBI3020, is the first dual-payload ADC developed from Innovent’s proprietary DuetTx dual-payload ADC platform. It targets CEACAM5 and comprises two payloads that have been clinically validated. CEACAM5 is a cell-surface glycoprotein involved in cell adhesion, invasion, and metastasis of cancer cells. It is overexpressed in solid tumors like colorectal cancer, non-squamous lung cancer, gastric cancer, and pancreatic cancer, but shows limited expression in healthy tissues, making it a potentially safe and promising therapeutic target. 

The other company with its dual-payload ADC candidate set for phase 1 trials is Chengdu Kanghong; its asset, KH815, is a TROP2-targeting molecule with topoisomerase 1 inhibitor and RNA polymerase 2 inhibitor payloads. It was originally expected to start its phase 1 trial in April, but it seems that the study has yet to begin recruiting patients.  

Elsewhere in the dual-payload ADC world, there are dozens of candidates in preclinical development, and companies are beginning to engage in collaborations regarding these candidates. For example, Lonza’s Synaffix announced in September that it had entered into a licensing agreement with Qurient, a South Korean company, for the development of a dual-payload ADC consisting of Synaffix’s exatecan-based technology and Qurient’s CDK7 inhibitor. And, more recently, in October, Debiopharm partnered with a South Korean artificial intelligence (AI) discovery company to develop next-generation, dual-payload ADCs designed to overcome acquired resistance mechanisms in difficult-to-treat cancers.  

Dual-payload PDCs: Avacta Therapeutics currently leading the way in the field 

Meanwhile, in the dual-payload PDC field, Avacta Therapeutics stands out as the leading company helping to drive this emerging drug strategy forward with its dual-payload pre|CISION technology. 

“We have invented a linker technology that allows the attachment of two individual molecules of drugs that will be released from the pre|CISION peptide with a single FAP [fibroblast activation protein] cleavage event in the tumor microenvironment,” Avacta’s chief executive officer (CEO), Christina Coughlin, told Labiotech. 

She further explained that Avacta’s proprietary pre|CISION peptide is the basis of a drug delivery platform that is targeted to FAP in solid tumors. “FAP is a protease expressed in the stromal compartment in 90% of human solid tumors on the extracellular surface. Importantly, the extracellular release of the payloads by FAP has two key aspects: one, the pre|CISION peptide is highly selective for FAP and thus is not released by any other protease, thus being a highly specific tumor release mechanism, and, two, given the extracellular release, the bystander effect is highly active in these therapies, meaning that both FAP-positive cells in the stroma and FAP-negative tumor cells are killed by the released payload.”  

Avacta, which already has a single-payload PDC candidate in the clinic, recently presented first preclinical data showing that its dual-payload pre|CISION technology has demonstrated robust FAP-selective delivery and potent anti-tumor activity across multiple complementary payload combinations.  

“The backbone of cancer therapy has always been combinations, as cancer cells are very effective at developing resistance mechanisms, even to the most effective cancer therapies,” commented Coughlin. “As a first entry in this market, Avacta has developed a combination therapy based on a widely used mechanism, a topoisomerase I inhibitor – for example, exatecan or SN38 are two options – that is combined with inhibition of a key resistance mechanism in the DNA Damage Repair (DDR) pathway.” 

This combination approach is designed to allow the potent anticancer drug to work by creating breaks in the DNA or the genetic code, whilst simultaneously inhibiting the resistance mechanism of this drug. “These kinds of combination therapies will allow us to target those cancers with the highest likelihood of developing resistance to topoisomerase I inhibitors. The exciting aspect of this new platform approach is that the combination opportunities are endless, and our ability to plot the most effective combinations will be informed by AI, leveraging further our strategic collaboration with Tempus and planning for rational combination therapies based on resistance mechanisms that are observed in human cancers,” stressed Coughlin.  

She told Labiotech that Avacta’s dual-payload PDC candidate is anticipated to be filed with the health authorities in 2027.  

Taking a double hit at cancer cells: The rise of “combination” therapies  

As Coughlin expressed, cancer cells have always been very good at overcoming cancer therapies due to resistance mechanisms. This is exactly why combination approaches to treating cancer, particularly solid tumors, have gained traction in recent years: just think about the surge in bispecific antibody development in the last few years or so. 

“…We have seen that immune molecules with two specificities have a greater impact than a single therapeutic – for example, an antibody with a single specificity.  As we know that cancer cells are capable of acquiring resistance mechanisms quite rapidly, the combination therapy is designed to overcome this aspect of cancer cells and is anticipated to be more highly effective in certain malignancies over single payload delivery,” commented Coughlin. 

Dual-payload ADCs and PDCs could well be the “next big things” in cancer treatment. With dual-payload ADCs already in the clinic and plenty more in preclinical development, and with Avacta’s PDC expected to enter clinical trials in around two year’s time, it might not be long before we see a surge in dual-payload candidates just as we did with bispecifics – but we will have to wait and see. 

Ultimately, next-generation dual-payload drugs aim to improve tumour eradication, delay or prevent resistance, and provide more potent, versatile treatments for cancer patients. And, as more candidates advance through preclinical and early clinical studies, they also highlight the growing potential of precision combination therapies in oncology.