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SEZ6-Targeted PET Imaging and Alpha-Particle Radioimmunotherapy is Effective for Detection and Treatment of Small
Behnaz Ghaemi1, Colleen P Olkowski2, Falguni Basuli3
1National Cancer Institute Bethesda, Maryland United States.
Abstract:
Small cell lung cancer (SCLC) remains one of the most lethal malignancies, with a five-year survival of <10% despite advances in treatment. Seizure-related gene 6 (SEZ6), a type I transmembrane protein preferentially expressed in neuroendocrine tumors, has recently emerged as a promising therapeutic target, supported by clinical activity of SEZ6-targeted antibody-drug conjugates in relapsed SCLC. Here, we developed and evaluated a humanized anti-SEZ6 monoclonal antibody for SEZ6-targeted positron emission tomography (PET) imaging and α-particle radioimmunotherapy. Immunohistochemistry of patient tissues confirmed strong, stage-independent SEZ6 expression. Cell-based studies demonstrated high SEZ6 receptor densities, supporting high-affinity antibody binding and rapid receptor-mediated internalization. [89Zr]Zr-DFO-SEZ6-Ab administered at low antibody mass exhibited rapid hepatosplenic clearance with minimal tumor uptake despite high intratumoral levels. This pattern was consistent with active ectodomain shedding and local accumulation of soluble antigen within the tumor microenvironment, creating an extracellular antigen sink and limiting effective target engagement. Increasing the antibody mass overcame this barrier, dramatically increasing tumor uptake in xenografts. Treatment with [225Ac]Ac-Macropa-SEZ6-Ab induced complete tumor regression, while co-administration of the ATR inhibitor berzosertib enhanced efficacy at lower radioactivity doses without added toxicity. Together, these findings identify tumor-localized SEZ6 shedding as a biological barrier to SEZ6-targeted therapy, define dosing strategies to overcome it, and demonstrate potent antitumor activity of SEZ6-directed α-particle radioimmunotherapy in SCLC.
Insights
Small cell lung cancer (SCLC) therapy faces challenges. Targeting Seizure-related gene 6 (SEZ6) with antibody-drug conjugates shows promise, but antigen shedding can be a barrier. Strategies to overcome this barrier and potent radioimmunotherapy were demonstrated.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Imaging
Background:
- Small cell lung cancer (SCLC) has a poor prognosis despite treatment advances.
- Seizure-related gene 6 (SEZ6) is a promising therapeutic target in neuroendocrine tumors, including SCLC.
- SEZ6-targeted antibody-drug conjugates have shown clinical activity in relapsed SCLC.
Purpose of the Study:
- To develop and evaluate a humanized anti-SEZ6 monoclonal antibody for PET imaging and alpha-particle radioimmunotherapy in SCLC.
- To investigate SEZ6 expression in patient tissues and its role in SCLC.
- To define strategies to overcome biological barriers in SEZ6-targeted therapy.
Main Methods:
- Immunohistochemistry to assess SEZ6 expression in patient tissues.
- Cell-based assays to evaluate SEZ6 receptor density, antibody binding, and internalization.
- PET imaging with [89Zr]Zr-DFO-SEZ6-Ab to assess biodistribution and tumor uptake.
- Alpha-particle radioimmunotherapy with [225Ac]Ac-Macropa-SEZ6-Ab, alone and in combination with berzosertib.
Main Results:
- SEZ6 is highly expressed in SCLC, independent of stage.
- Low antibody doses showed limited tumor uptake due to SEZ6 ectodomain shedding, creating an antigen sink.
- Increased antibody mass successfully overcame the shedding barrier, enhancing tumor uptake in xenografts.
- SEZ6-targeted alpha-particle radioimmunotherapy induced complete tumor regression.
- Combination therapy with berzosertib enhanced efficacy at lower doses without increased toxicity.
Conclusions:
- Tumor-localized SEZ6 shedding is a significant biological barrier to effective SEZ6-targeted therapy in SCLC.
- Optimized dosing strategies can overcome antigen shedding and improve therapeutic delivery.
- SEZ6-directed alpha-particle radioimmunotherapy demonstrates potent antitumor activity in SCLC models.
- Combined radioimmunotherapy and ATR inhibition offers a promising therapeutic approach for SCLC.
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