Antibody-drug conjugates (ADCs) remain one of the most active areas of oncology drug development, integrating monoclonal antibody specificity with highly potent cytotoxic payloads. Advances in linker chemistry, site-specific conjugation, and next-generation payloads (particularly topoisomerase I inhibitors and microtubule-disrupting agents) have improved pharmacokinetics, stability, and therapeutic index. As a result, ADC pipelines are expanding rapidly across breast, lung, gastrointestinal, and gynecologic cancers.
In 2026, multiple late-stage ADC candidates targeting HER2, TROP2, B7-H3, Claudin18.2, and other tumor-associated antigens are approaching pivotal data readouts and regulatory decisions. These programs are expected to influence treatment algorithms in biomarker-selected populations and further establish ADCs as a core modality in precision oncology.
Pivekimab sunirine (PVEK) is an investigational antibody-drug conjugate (ADC) that targets CD123, a cell surface protein overexpressed in several hematologic malignancies, including blastic plasmacytoid dendritic cell neoplasm (BPDCN) and acute myeloid leukemia (AML). CD123, the alpha chain of the interleukin-3 receptor (IL-3Rα), is highly expressed on malignant plasmacytoid dendritic cells, making it a clinically relevant target in BPDCN.
PVEK consists of a humanized anti-CD123 monoclonal antibody linked to a potent DNA-alkylating payload. Upon binding to CD123-expressing cells, the ADC is internalized and releases its cytotoxic agent, leading to targeted cell death while sparing healthy tissues with low or absent CD123 expression. This targeted approach is designed to improve therapeutic outcomes while minimizing systemic toxicity.
AbbVie submitted a Biologics License Application (BLA) for PVEK to the FDA in September 2025 based on data from the global Phase 1/2 CADENZA trial. The study evaluated PVEK as monotherapy in patients with BPDCN, an aggressive hematologic malignancy with limited treatment options and poor prognosis. The compound also holds Breakthrough Therapy designation from the FDA, granted in October 2020 for relapsed or refractory BPDCN.
Izalontamab brengitecan (iza-bren; BL-B01D1) is a bispecific ADC targeting epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3). It is engineered to simultaneously bind both receptors, which are co-expressed in multiple epithelial malignancies and implicated in tumor proliferation, survival signaling, and therapeutic resistance. The ADC is conjugated to a topoisomerase I inhibitor payload, enabling targeted delivery of a DNA-damaging agent following receptor-mediated internalization.
The dual-targeting design is intended to inhibit EGFR- and HER3-driven signaling while addressing compensatory HER3 upregulation, a known resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs). Upon binding, the ADC-receptor complex undergoes internalization, intracellular payload release, and induction of genotoxic stress, leading to tumor cell apoptosis.
On August 18, 2025, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation (BTD) to iza-bren for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions or exon 21 L858R mutations, in patients who have progressed following EGFR TKI and platinum-based chemotherapy. The designation was supported by efficacy and safety data from three ongoing clinical trials: BL-B01D1-101 and BL-B01D1-203 conducted in China, and the global BL-B01D1-LUNG-101 study across the United States, Europe, and Japan.
Rinatabart sesutecan (Rina-S; GEN1184) is an investigational ADC composed of a human monoclonal antibody targeting folate receptor alpha (FRα), a hydrophilic protease-cleavable linker, and an exatecan-derived topoisomerase I inhibitor payload. FRα is overexpressed in multiple epithelial malignancies, including endometrial cancer (EC), and represents a validated tumor-associated antigen with limited expression in normal tissues.
Rina-S is designed to bind FRα-expressing tumor cells, undergo receptor-mediated internalization, and release the cytotoxic payload intracellularly following linker cleavage. The exatecan payload induces DNA damage through inhibition of topoisomerase I, resulting in replication stress and apoptosis.
Rina-S is now advancing in a Phase 3 trial in endometrial cancer, as well as a Phase 3 trial in platinum-resistant ovarian cancer. On August 26, 2025, the U.S. FDA granted Breakthrough Therapy Designation (BTD) for Rina-S in adults with recurrent or progressive endometrial cancer following platinum-based chemotherapy and PD-(L)1 therapy, supporting expedited development in this high unmet-need population.
Trastuzumab pamirtecan (BNT323/DB-1303) is an investigational third-generation ADC targeting HER2. The molecule consists of a HER2-directed monoclonal antibody conjugated to a topoisomerase I inhibitor payload. The ADC is designed to deliver cytotoxic payload selectively to HER2-expressing tumor cells, including both HER2-positive and HER2-low malignancies.
On September 5, 2025, BioNTech and DualityBio announced that a Phase 3 trial met primary endpoint of progression free survival in HER2-positive metastatic or unresectable breast cancer. The randomized study (NCT06265428) compared trastuzumab pamirtecan with trastuzumab emtansine (T-DM1) in patients with HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and taxane-based chemotherapy. Based on these results, DualityBio plans to engage with the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) regarding submission of a Biologics License Application (BLA).
Trastuzumab pamirtecan is also being evaluated in the global Phase 3 DYNASTY-Breast02 trial (NCT06018337) in patients with hormone receptor-positive, HER2-low metastatic breast cancer, as well as in an ongoing Phase 1/2 study in advanced solid tumors. The program previously received U.S. FDA Fast Track and Breakthrough Therapy designations for endometrial cancer.
Sonesitatug Vedotin, also known as AZD0901 or CMG901, is a Claudin18.2-directed AD) designed for the treatment of gastric, gastroesophageal junction (GEJ), and other Claudin18.2-expressing malignancies. Claudin18.2 is a tight junction protein selectively expressed in gastric mucosa and retained in a subset of gastric, GEJ, and pancreatic cancers, making it a tumor-associated antigen of therapeutic interest.
Sonesitatug vedotin consists of a monoclonal antibody targeting Claudin18.2 conjugated to the microtubule inhibitor monomethyl auristatin E (MMAE). Upon binding to Claudin18.2 on the tumor cell surface, the ADC undergoes internalization and intracellular release of MMAE, leading to microtubule disruption and apoptosis. In addition to direct cytotoxicity, preclinical studies demonstrate that AZD0901 mediates antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and bystander killing, supporting multiple mechanisms of anti-tumor activity.
AZD0901 is currently being evaluated in the Phase III CLARITY Gastric 01 trial (NCT06346392), which compares AZD0901 monotherapy with standard treatment options in patients with previously treated advanced or metastatic gastric or GEJ cancer expressing Claudin18.2.
Ifinatamab deruxtecan (I-DXd) is an investigational ADC targeting B7-H3, a transmembrane protein of the B7 family that is overexpressed in multiple solid tumors, including small cell lung cancer (SCLC). B7-H3 expression has been associated with poor prognosis, and no B7-H3–directed therapies are currently approved.
I-DXd is composed of a humanized anti–B7-H3 IgG1 monoclonal antibody conjugated via a cleavable tetrapeptide-based linker to a topoisomerase I inhibitor payload (an exatecan derivative, DXd), using Daiichi Sankyo’s DXd ADC technology. Following antigen binding and internalization, linker cleavage enables intracellular release of the cytotoxic payload, inducing DNA damage and tumor cell death.
In August 2025, the U.S. FDA granted Breakthrough Therapy Designation (BTD) to ifinatamab deruxtecan for the treatment of adult patients with extensive-stage small cell lung cancer whose disease has progressed on or after platinum-based chemotherapy. The designation was based on data from the Phase 2 IDeate-Lung01 trial, with supportive evidence from the Phase 1/2 IDeate-PanTumor01 study. Ifinatamab deruxtecan has also received orphan drug designation for SCLC in the United States, European Union, Japan, and Taiwan.
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