Selected Articles from This Issue

CanAg is a highly expressed cancer-associated antigen with minimal normal tissue expression, making it an attractive target for antibody drug conjugates (ADCs). Here, Huang and colleagues describe IKS04, a novel CanAg-targeted ADC using a pyrrolobenzodiazepine payload capable of killing both proliferating and non-proliferating cells. The high target expression requires a sufficient antibody dose to achieve adequate tumor uptake and distribution. Coadministration of unconjugated antibody with the IKS04 ADC improved pharmacokinetics, increased tumor tissue penetration, and enhanced in vivo efficacy. Strategies to improve tumor delivery by increasing the antibody dose have the potential to increase the clinical efficacy of ADCs.This study addressed the need for new targeted therapies for solid tumors by developing XB010, a novel antibody-drug conjugate (ADC) directed against the oncofetal antigen 5T4, which is overexpressed in many cancers but minimally present in normal tissues. Researchers used SMARTag site-specific conjugation and a tandem-cleavage linker to enhance drug stability and tolerability. XB010 showed potent, selective cytotoxicity and durable tumor regression in multiple xenograft and patient-derived models, with acceptable safety profiles in rats and primates. These results suggest XB010 as a promising therapeutic candidate for 5T4-expressing solid tumors and support its clinical evaluation.To potentiate the curative potential of autologous stem cell transplantation (ASCT) for high-risk non-Hodgkin lymphoma (NHL), the Seattle radioimmunotherapy team evaluated the safety of adding B9E9-Fusion Protein, a tetrameric single-chain anti–CD20–streptavidin fusion protein, in pretargeted radioimmunotherapy (PRIT) with dose escalated yttrium-90 (90Y) before BEAM and ASCT. Although termination of funding ended accrual prematurely, the results show that this novel combinatorial treatment approach is well tolerated without additional clinically meaningful toxicity over standard ASCT. The blood and urine PK studies and gamma-camera imaging support minimal uptake at non-target organs and substantiate quick excretion of 2nd step radioligand 90Y-DOTA-biotin via the urine. Despite newly approved therapies for NHL, boosted ASCT approaches with B9E9-Fusion Protein PRIT hold potential to improve outcomes for high-risk NHL patients due to the high radiosensitivity of hematologic malignancies and how well PRIT with B9E9-Fusion Protein and 90Y-DOTA is tolerated.Myeloid cells drive immunosuppression and therapy resistance in glioblastoma (GBM). This study targets CD11b+ tumor-associated myeloid cells using α-emitting radiopharmaceutical therapy (αRPT), alone or with immune checkpoint inhibitors (ICI). A radiolabeled anti-CD11b antibody (with 89Zr or 225Ac) showed effective tumor targeting and defined a safe dose (∼0.55 kBq/100 μg). The combination of CD11b-targeted αRPT and ICI improved overall survival in a glioma mouse model, with 50% long-term survivors and evidence of antitumor immunity upon rechallenge. These findings support CD11b-targeted αRPT as a promising GBM treatment strategy.