In recent years, cancer immunotherapy—particularly therapies based on PD-L1 inhibition—has fundamentally reshaped the oncology treatment landscape. As a key pan-tumor immune checkpoint target, PD-L1 is widely expressed across multiple solid tumors, including non-small cell lung cancer (NSCLC), squamous cell carcinoma, colorectal cancer, triple-negative breast cancer, and melanoma. In several tumor types, the overall PD-L1 positivity rate (high, intermediate, and low expression combined) exceeds 50%, reaching up to 70% in NSCLC, while expression in normal tissues remains relatively limited.

Despite these advances, PD-(L)1–based therapies face well-recognized clinical limitations. Treatment efficacy is highly dependent on PD-L1 expression levels, and both primary and acquired resistance occur at substantial rates. As a result, a large proportion of patients ultimately enter a therapeutic dead-end in the post-immunotherapy setting, with limited effective options available.

Against this backdrop, antibody–drug conjugates (ADCs) have emerged as one of the most important strategies in modern oncology, leveraging the synergy between precise tumor targeting and highly potent cytotoxic payloads. The integration of the PD-L1 target with the ADC platform has given rise to PD-L1–directed ADCs, representing a meaningful shift from single-mechanism therapies to a multi-modal treatment paradigm. By combining targeted therapy, immunotherapy, and chemotherapy within a single molecular construct, PD-L1 ADCs mark a significant evolution in anticancer drug design.

Mechanism of Action of PD-L1 ADC

PD-L1 ADCs are engineered molecules composed of an anti-PD-L1 monoclonal antibody covalently linked to a cytotoxic payload via a stable linker. Their design capitalizes on the dual biological role of PD-L1, which functions not only as an immune checkpoint molecule but also as a tumor-associated antigen.

Figure 1. PD-L1-ADC mechanism of action, source: reference [1]

This strategy enables a triple mechanism of action that addresses key limitations of conventional therapies:

◆ Sustained immune checkpoint blockade
The antibody component retains its ability to inhibit the PD-1/PD-L1 signaling axis, thereby preserving T-cell activation and maintaining antitumor immune responses.

◆ Targeted cytotoxic killing
Upon binding to PD-L1 expressed on tumor cells, the ADC is internalized, releasing a highly potent payload—such as the microtubule inhibitor monomethyl auristatin E (MMAE)—to directly induce tumor cell apoptosis.

◆ Bystander effect to expand therapeutic coverage
Cleavable linkers enable the release of payloads within the tumor microenvironment, allowing them to diffuse into neighboring cells with low or heterogeneous PD-L1 expression. This bystander effect significantly broadens antitumor activity and improves efficacy against refractory or heterogeneous lesions.

Through this integrated approach, PD-L1 ADCs offer a compelling solution to immune resistance and tumor heterogeneity, positioning them as a promising next-generation modality in the treatment of solid tumors.

Recent developments in PD-1 ADCs

Currently, only two PD-1 ADC candidates have progressed to clinical trials - PF-08046054 (SGN-PDL1V) and HLX43.

PF-08046054 (SGN-PDL1V)

PF-08046054, also known as SGN-PDL1V or PDL1V, is a PD-L1–targeted ADC developed by Pfizer. It is the first PD-L1 ADC to enter clinical development worldwide and remains the most advanced program in this class, having progressed to Phase III clinical evaluation (NCT07144280).

SGN-PDL1V is composed of an anti-PD-L1 monoclonal antibody conjugated to the MMAE via a protease-cleavable mc-vc (maleimidocaproyl–valine–citrulline) linker, with a drug-to-antibody ratio (DAR) of 4. This molecular design enables selective delivery of MMAE to PD-L1–expressing tumor cells, with antitumor activity mediated through direct cytotoxicity, a bystander killing effect, and induction of immunogenic cell death.

Data from a Phase I study in patients with advanced solid tumors (NCT05208762) were presented at the 2025 ASCO Annual Meeting. All enrolled patients had previously received PD-1/PD-L1 immune checkpoint inhibitors as well as taxane-based chemotherapy. Across the overall study population, SGN-PDL1V achieved an objective response rate (ORR) of 26.7%, which increased to 32% in PD-L1–positive patients. Confirmed ORRs were comparable between squamous and non-squamous tumor subtypes, at 33.3% and 31.6%, respectively. At a median follow-up of 10.0 months, the median duration of response (DOR) was 7.8 months. [2]

Importantly, no objective responses were observed in patients with low PD-L1 expression (<1%). All six patients in this subgroup had a response rate of 0%, highlighting the continued relevance of PD-L1 expression as a predictive biomarker for PD-L1–directed ADC therapy.

HLX43

HLX43, developed by Henlius, is a PD-L1-targeting ADC, composed of an engineered version of the anti-PD-L1 humanized IgG1 antibody (HLX20), conjugated via a next-generation linker to acamptothecin-based toxin. The DAR is around 8. As of now, Phase 2 global multi-regional clinical trials of HLX43 have been initiated in China, the U.S., Japan, and Australia, with the first subjects dosed in China and the U.S.

At the 2025 World Conference on Lung Cancer (WCLC), updated results from the Phase I study of HLX43 were presented in patients with advanced or metastatic NSCLC who had previously received standard therapies.

A total of 56 NSCLC patients (safety set, SS; ITT=56, RES=54) were included with a median follow-up of 9.0 months (data cutoff: June 28, 2025). Overall, HLX43 demonstrated an objective response rate (ORR) of 37.0% and a disease control rate (DCR) of 87.0%, with a median progression-free survival (mPFS) of 5.4 months. Importantly, efficacy was observed across key subgroups: squamous NSCLC (ORR 28.6%), non-squamous NSCLC (ORR 46.2%), EGFR wild-type (ORR 46.7%) and mutant (ORR 45.5%), and in patients who had failed prior docetaxel (≥3L) therapy (ORR 30.0%). In the EGFR wild-type cohort at the 2.5 mg/kg dose, a confirmed ORR of 60.0% was reported. Notably, patients with brain metastases achieved an ORR of 36.4% and DCR of 100%. Efficacy was consistent irrespective of PD-L1 expression levels (TPS ≥1% ORR 34.4% vs TPS <1% ORR 38.1%), supporting biomarker-independent activity. [3]

Beyond PD-L1 ADCs: The Emergence of PD-L1 Bispecific ADCs

In addition to conventional PD-L1–targeted ADCs, several companies are pursuing differentiated strategies by developing PD-L1 bispecific ADCs. By simultaneously targeting PD-L1 and a second tumor-associated antigen, these next-generation molecules aim to broaden tumor coverage, reduce reliance on PD-L1 expression alone, and enhance overall antitumor efficacy.

DB-1419 (B7-H3 / PD-L1)

DB-1419 is a bispecific ADC composed of a humanized IgG1 antibody targeting both B7-H3 and PD-L1. It is conjugated to a proprietary DNA topoisomerase I inhibitor (P1003) through a cleavable maleimide tetrapeptide linker, with an average DAR of approximately 8.

In preclinical studies, DB-1419 demonstrated strong antitumor activity across multiple tumor models, along with favorable pharmacokinetic and safety profiles. Based on these results, DB-1419 is currently being evaluated in an ongoing Phase I/IIa clinical trial in patients with advanced solid tumors (NCT06554795). [4]

IBI3014 (TROP-2 / PD-L1)

IBI3014 is a dual-targeting ADC directed against TROP-2 and PD-L1. It consists of a humanized bispecific antibody linked to a novel DNA topoisomerase I inhibitor, NT1, via a cleavable linker.

In cell line–derived xenograft (CDX) models with varying levels of TROP-2 and PD-L1 expression, IBI3014 showed stronger cytotoxic activity than benchmark ADCs and demonstrated activity across a broader range of tumor types. The molecule remained stable in both mice and non-human primates and was well tolerated in monkeys, with a highest non-severely toxic dose (HNSTD) of 50 mg/kg. Its dual-targeting design offers the potential to improve efficacy while maintaining a favorable safety profile. [5]

JSKN022 (ITGB6/8 / PD-L1)

JSKN022 is a bispecific single-domain antibody–based ADC that targets PD-L1 and integrin ITGB6/8. The antibody was generated using antibody-directed evolution and is conjugated through site-specific glycosylation to produce a homogeneous and stable ADC with a DAR of 4. This design aims to improve molecular consistency and controlled drug delivery. [6]

Conclusion

Whether evolving from established PD-L1 inhibitors, advancing ADC technologies, or incorporating bispecific and multispecific antibody designs, this field reflects a broader trend toward more precise, potent, and versatile cancer treatments. Together, these converging strategies underscore the growing role of PD-L1–based ADC platforms as a key driver of next-generation innovation in oncology.

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References:
[1] Wang, J., Chen, Z., Wu, Y., Zhang, W., & Awadasseid, A. (2025). Innovations in cancer immunotherapy with PD-1 antibody-drug conjugates and their antitumor mechanisms. Biomedicine & Pharmacotherapy, 191, 118517. https://doi.org/10.1016/j.biopha.2025.118517
[2] Elisa Fontana et al. Interim results of PDL1V (PF-08046054), a vedotin-based ADC targeting PD-L1, in patients with NSCLC in a phase 1 trial.. J Clin Oncol 43, 8611-8611(2025). DOI:10.1200/JCO.2025.43.16_suppl.8611
[3] https://www.henlius.com/en/NewsDetails-5441-26.html The Updated Clinical Results for PD-L1 ADC HLX43 at the 2025 WCLC, Demonstrate Outstanding Efficacy in NSCLC
[4] Li C, Yao J, Yang J, Zhang Y, Qiu Y, Zhu Z, Hua H. Preclinical Evaluation of DB-1419, a Novel Bifunctional and Bispecific Anti-B7-H3 × PD-L1 Antibody-Drug Conjugate. Clin Cancer Res. 2025 Aug 14;31(16):3581-3593. doi: 10.1158/1078-0432.CCR-25-0634. PMID: 40499141; PMCID: PMC12351279.
[5] https://aacrjournals.org/cancerres/article/85/8_Supplement_1/344/755729/Abstract-344-IBI3014-a-TROP2xPD-L1-bi-specific-ADC
[6] https://aacrjournals.org/cancerres/article/85/8_Supplement_1/5450/758268