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When ADCs Team Up with Immune Modulators to Fight Cancer

Campbell Bunce, Chief Scientific Officer (CSO) and Cambridge Site Head at Abzena

Antibody-drug conjugates (ADCs) already sit close to the top of oncological treatments because, unlike many other therapies, they can selectively target and eradicate tumour cells. As the industry has refined this therapeutic approach, we’re now seeing ADCs being integrated with the capacity to modulate the immune system. This new addition to the ADC arsenal marks a progressive shift, bolstering the fight against cancer with a focus on increasing immunotherapy potency.

What if we used ADCs to ramp up the immune response?

ADCs are great examples of precision cancer therapy because they exploit the targeting capabilities of monoclonal antibodies to deliver cytotoxic agents directly to cancer cells. By bringing together the specificity of antibodies with the potency of chemotherapy agents, ADCs have the potential to sidestep the toxicity that comes with the systemic delivery of conventional chemotherapy.

Traditional ADC payloads have relied on cytotoxins, such as tubulin inhibitors and DNA-damaging agents, to kill cancer cells. And while their progress and success are undeniable – with research leading to diverse payloads, like inhibitory RNAs, Bcl-xL inhibitors, niacinamide phosphate ribose transferase (NAMPT) inhibitors and carmaphycins1 – there’s still room to broaden the scope of this approach and push for better efficacy.

So, to keep ADC innovation moving forward, the industry is turning its attention to molecules that can modulate the immune system. Off the back of immunotherapy’s success, ADC scientists have been working to merge the benefits from both fields. This has led to an integration of immune-modulating agents into ADCs that can make use of inherent and powerful defences of the body that are already in place.

These immune-modulating ADCs can enhance the immune response against cancer and drive a range of immune activities to eradicate tumour cells and potentially prevent cancer recurrence. If we can fine-tune this new wave of ADCs, they would represent a new class of payloads that address the complex but important role the immune system can play in treating cancer.

Combining ADCs with immune-stimulating payloads

To get a better understanding of how immune modulators work, let’s look at a particular target: toll-like receptors (TLRs), the sentinels of immune surveillance that might just turn the tables on cancer.

TLR agonists have attracted a great deal of attention as they should be able to make use of the TLR surveillance system and ramp up the body’s immune attack on cancer. By activating TLRs, these molecules should unlock the powerful innate immune system and boost anti-tumour responses in several cancer types, including lung cancer, melanoma, leukaemia and glioma.2 This activation not only curbs tumour growth but can also prime the adaptive immune system for a stronger and more direct assault.

This is exciting for good reason in the world of cancer immunotherapy. TLR agonists could theoretically turn “cold” tumours, which typically evade immune detection, into “hot” ones that the immune system can target. An outcome like this would be huge for patients who are poor responders to single immune checkpoint inhibitors, as TLRs could amplify the response to such therapies and drastically change the outcome. Among the TLR family, there’s a particular focus on TLR7, TLR8 and TLR9, as these have shown great promise in recent research efforts.1

TLR8 agonists, for example, have been shown to boost anti-tumour responses by improving dendritic cell (DC) and macrophage antigen presentation and promoting CD8+ T cell proliferation.2,3 However, like many immunotherapies, systemic TLR8 administration often comes with adverse side effects, restricting dose and thus its use in the clinic.

For ADC scientists, the next step was obvious: to reduce the toxicity of TLR agonists by conjugating them with an antibody – since targeted delivery should limit adverse effects and open up the therapeutic window. In 2021, a team came up with an immune-stimulating antibody conjugate (ISAC) that incorporated a dual-acting TLR7/8 agonist tethered to a HER2-specific antibody.4 Their engineered ADC relied on Fcγ-receptor-mediated phagocytosis and TLR signalling to trigger a potent myeloid-driven response against tumour cells, followed by the activation of T-cell immunity. Unlike TLR agonists alone, systemic administration of HER2-targeted ISACs – in mouse models at least – was well tolerated and led to tumour regression and immunological memory.

Building on checkpoint inhibitors for a truly dual approach

Checkpoint inhibitors have become a cornerstone in oncology. These therapies “take the brakes off” the immune system by targeting checkpoints; blocking the PD-1/ PD-L1 interaction via anti-PD-L1 antibodies, for example, is a well-studied and successful strategy.5 However, despite their success, checkpoint inhibitors alone often rely on patients with tumours permeated by immune cells, but their efficacy is less certain for those lacking such infiltration.

This is where we see the power of combining ADCs with checkpoint inhibitors. This process capitalises on ADC-induced immunogenic cell death (ICD), where the released damage-associated molecular patterns (DAMPs) promote antigen-presenting cell activation and T-cell cross-presentation.6 This union of ADC and checkpoint inhibitors can enhance T-cell infiltration to the tumour microenvironment and boost antitumour immunity.7,8

In 2021, we saw the ADC dubbed HE-S2. This construct linked an anti-PD-L1 THIOMAB (an engineered antibody with a reactive thiol group that allows for site-specific drug conjugation)9 to the immunomodulator D18 via a sensitive redox-cleavable linker.10  Site-specific drug conjugation platforms are at the front of the successful wave of ADCs.  These platforms, such as ThioBridge by Abzena, allow for better control of drug conjugation with enhanced stability and efficiency.  Regarding HE-SE, this novel conjugate not only blocks PD-L1 but also delivers D18 directly to tumour sites, where it stimulates immune cell infiltration, activates TLR7 and TLR8 and upregulates PD-L1 to improve tumour sensitivity to a checkpoint blockade. Importantly, HE-S2 circumvents the systemic toxicity seen with other checkpoint inhibitor therapies in these early studies. The authors suggest that HE-S2 could show promise beyond oncology, suggesting potential for chronic viral infections like HIV or HBV, given its targeted immunomodulatory effects, which include activating dendritic cells through TLR7/8 and inciting inflammatory cytokines like IFN-γ.

We’ve also seen a good number of clinical trials that look at ADCs combined with checkpoint inhibitors, but these have so far had mixed results. The KATE2 study (NCT02924883) found that combining the checkpoint inhibitor atezolizumab with the ADC trastuzumab emtansine (Kadcyla) (T-DM1) offered no significant survival benefits in HER2-positive breast cancer patients and led to higher toxicity, causing the trial to end early.11 Another trial (NCT03032107) showed moderate efficacy for T-DM1 and pembrolizumab. However, a phase 1b study (NCT03523572) pairing trastuzumab deruxtecan (T-DXd) with nivolumab did not meet the higher efficacy benchmarks set by T-DXd alone, despite substantial response rates.12 Meanwhile, the BEGONIA trial (NCT03742102), which is ongoing and assessing various combinations of the PD-L1 inhibitor durvalumab (Imfinzi), demonstrated the ADC datopotamab deruxtecan (Dato-DXd), paired with durvalumab, has strong activity, regardless of PD-L1 expression.13,14

ADCs with immune modulators are moving medicine forward

As oncological treatment evolves, the combination of ADCs with immune modulation tools seems to be a promising path. As we look ahead, we can see there is a need for a tailored approach that considers the heterogeneous nature of tumours and patient-specific needs. Utilising site-specific, versatile bioconjugation platforms, like ThioBridge are bringing about new approaches that can aid in improving ADC development that can lead to more effective oncology treatments. The growing body of research in the area continues to move the scientific community forward as we refine these technologies to meet the needs of safety, specificity and efficacy. The potential of ADCs in combination with immune modulation is clear, but it is with careful optimism and continued investigation that we advance.


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2. Sun, H. et al. Targeting toll-like receptor 7/8 for immunotherapy: recent advances and prospectives. Biomark. Res. 10, 89 (2022).

3. Kim, H. et al. Polymeric nanoparticles encapsulating novel TLR7/8 agonists as immunostimulatory adjuvants for enhanced cancer immunotherapy. Biomaterials 164, 38–53 (2018).

4. Ackerman, S. E. et al. Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity. Nat. Cancer 2, 18–33 (2021).

5. Akinleye, A. & Rasool, Z. Immune checkpoint inhibitors of PD-L1 as cancer therapeutics. J. Hematol. Oncol.J Hematol Oncol 12, 92 (2019).

6. Müller, P., Rios-Doria, J., Harper, J. & Cao, A. Combining ADCs with Immuno-Oncology Agents. in Innovations for Next-Generation Antibody-Drug Conjugates (ed. Damelin, M.) 11–44 (Springer International Publishing, 2018). doi:10.1007/978-3-319-78154-9_2.

7. Rosenberg, J. E. et al. LBA73 Study EV-103 Cohort K: Antitumor activity of enfortumab vedotin (EV) monotherapy or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC). Ann. Oncol. 33, S1441 (2022).

8. Hoimes, C. J. et al. Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. J. Clin. Oncol. 41, 22–31 (2023).

9. Chen, X. (Nancy), Nguyen, M., Jacobson, F. & Ouyang, J. Charge-based analysis of antibodies with engineered cysteines. mAbs 1, 563–571 (2009).

10.       He, L. et al. Immune Modulating Antibody-Drug Conjugate (IM-ADC) for Cancer Immunotherapy. J. Med. Chem. 64, 15716–15726 (2021).

11.       Emens, L. A. et al. Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial. Lancet Oncol. 21, 1283–1295 (2020).

12.       Hamilton, E. P. et al. 162O Primary analysis from DS8201-A-U105: A 2-part, open label, phase Ib trial assessing trastuzumab deruxtecan (T-DXd) with nivolumab (nivo) in patients (pts) with HER2-expressing advanced breast cancer. Ann. Oncol. 33, S196 (2022).

13.       Helwick, C. BEGONIA Trial Reports Activity With Datopotamab Deruxtecan Plus Durvalumab in Triple-Negative Breast Cancer – The ASCO Post. https://ascopost.com/issues/october-10-2022-supplement-breast-cancer-almanac/begonia-trial-reports-activity-with-datopotamab-deruxtecan-plus-durvalumab-in-triple-negative-breast-cancer/ (2022).

14.       Schmid, P. et al. Abstract PD10-03: BEGONIA: Phase 1b/2 study of durvalumab (D) combinations in locally advanced/metastatic triple-negative breast cancer (TNBC): Results from Arm 1 D + paclitaxel (P), Arm 2 D+P + capivasertib (C), and Arm 5 D+P + oleclumab (O). Cancer Res. 82, PD10-03 (2022).


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