Crees ZD, DiPersio JF, Persaud SP (2026) Making space for cures: conditioning for autologous hematopoietic stem cell gene therapies. Seminars in Hematology doi: 10.1053/j.seminhematol.2026.09.001
Objective: To define the role transplant conditioning regimens play in autologous gene therapy, including contrasting the goals of care in this setting with those for stem cell transplantation for malignancies.
Summary: The phosphatase CD45 and the tyrosine kinase CD117 are the most frequently targeted antigens in HSCT conditioning studies. CD45-SAP and CD117-SAP were both highly effective at depleting murine HSCs, enabling transplantation between major histocompatibility complex
DLL3 is a cell-surface protein highly expressed in several neuroendocrine cancers, particularly small-cell lung cancer (SCLC) and neuroendocrine prostate cancer (NEPC), with limited expression in normal adult tissues, making it a potential therapeutic target.
The authors developed novel anti-DLL3 antibodies using genetically engineered mice carrying human antibody gene repertoires, generating antibodies that recognize distinct DLL3 epitopes. They used our Fab-ZAP Mouse to assess antibody internalization and identify antibodies capable of delivering attached cytotoxic or radioactive payloads into tumor cells.
One antibody, TDI-Y-010, showed favorable properties for molecular imaging. Conjugated with zirconium-89 (⁸⁹Zr), it produced a PET imaging tracer that showed substantial tumor accumulation in human SCLC tumors in mice.
The authors also developed a therapeutic radioimmunoconjugate by labeling TDI-Y-010 with ¹⁷⁷Lu, a therapeutic radionuclide that delivers cytotoxic radiation to DLL3-positive cells. ¹⁷⁷Lu-TDI-Y-010 showed significant antitumor activity and improved survival in two SCLC models, while survival in an NEPC model was comparable to the control.
Overall, the study supports DLL3 as a promising target for molecular imaging and targeted radionuclide therapy, with selective tumor uptake and only mild, transient hematologic toxicity.
Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic joint inflammation and damage, and current treatments don’t work equally well for everyone.
Researchers identified a specific population of inflammatory immune cells in RA joints that express high levels of uPAR (PLAUR). These uPAR-high cells also produce inflammatory molecules such as IL-1β and CXCL8, making them attractive therapeutic targets.
The team developed anti-uPAR antibody-drug conjugates (ADCs) to selectively eliminate these harmful cells. The authors then used Fab-ZAP rat (IT-55) to test the internalization capacity of anti-mouse uPAR antibodies. Saporin (PR-01) and Fab-IgG-SAP (IT-67) were used as control.
ADCs carrying BCL-2 inhibitor payloads, selectively killed activated inflammatory monocytes and macrophages while sparing normal, resting immune cells. Treatment also reduced the release of the inflammatory cytokine CXCL8.
Because mouse immune cells express less uPAR, the researchers used an MMAF payload to demonstrate proof of concept in a mouse model. The anti-uPAR–MMAF conjugate reduced inflammatory uPAR-high macrophages by about 39% compared to the control treatment.
Overall, the study shows that targeted ADCs can selectively eliminate disease-causing immune cells, suggesting a promising new therapeutic strategy for RA and other autoimmune or inflammatory diseases.
Navarre S, Ishibashi MN, Nair A, Reyes-Torres I, Belabed M, Halasz L, Park MD, Mattiuz R, Ounadjela M, Gunset G, Mansilla-Soto J, Feucht J, Cabriolu A, Le Berichel J, Birbrair A, Eyquem J, Brown BD, Merad M, Sadelain M, Ahmed J (2026) Tumor irradiation promotes antigen dressing of dendritic cells to enhance CAR T cell persistence and efficacy in lung metastases. Nat Cancer 7(7):1104-1120. doi: 10.1038/s43018-026-01167-6 PMID: 42174275
Objective: To investigate strategies to selectively enhance CAR T cell activity at tumor sites to widen the therapeutic window.
Summary: Using syngeneic models of extensive metastatic lung adenocarcinoma and melanoma, the authors showed irradiation increased CAR T cell numbers within tumors but not in adjacent normal lung tissue that also expressed target antigen, conferring robust control of tumor without increased toxicity.
Usage: CD117 was combined with Streptavidin-ZAP (IT-27) and administered at 1 mg kg−1 per recipient to selectively deplete host hematopoietic stem and progenitor cells. In vivo administration of immunotoxin was performed by i.v. injections (300 μl).
Dib C, Queenan JA, Willner H, Swartzrock L, Charlesworth CT, Denis M, Davis JR, Mepani RJ, Ho K, Castro M, Wilson RC, Nakauchi H, Liu DR, Czechowicz A (2026) Restoration of the immune system with base editing and non-genotoxic conditioning in a Rag2 point-mutant mouse model. Mol Ther 34(7):4070-4083. doi: 10.1016/j.ymthe.2026.04.010 PMID: 41968583
Objective: To investigate therapy that would eliminate the risks associated with current hematopoietic stem cell (HSC) gene-modification and conditioning approaches.
Summary: The authors combined base editors, engineered virus-like particles, and non-genotoxic CD117-SAP conditioning to explore optimal curative treatment of severe combined immunodeficiency. Results showcased a significant advancement in reducing treatment-related toxicities while enabling disease correction.
Usage: Using a mouse model, Anti-CD117 was combined with Streptavidin-ZAP (IT-27) and administered at 1.5 mg/kg via intravenous injection 8 days before transplantation.
Okalova J, Alexander JS, Patel SR, Branella GM, Barichello de Quevedo C, Baldwin WH, Prince C, Chandrakasan S, Brown HC, Doering CB, Spencer HT (2026) Antimetabolites synergize with antibody drug conjugate-based non-genotoxic conditioning facilitating hematopoietic stem cell-directed lentiviral gene therapy. Mol Ther Adv doi: 10.1016/j.omta.2026.201780
Objective: To investigate the hypothesis that anti-CD117-sap is not effective as a single non-genotoxic conditioning agent in hematopoietic stem and progenitor cells (HSPCs)-directed lentiviral vector gene therapy for hemophilia A due to a lack of deep HSPC depletion in the bone marrow (BM).
Summary: The authors demonstrated how conditioning with non-genotoxic conditioning ADCs, such as Anti-CD117-SAP, causes cycling of residual HSPCs in the BM niche. There is potential of repurposing antimetabolites into these non-genotoxic conditioning regimens when combined with immune suppression to further target ADC-induced cycling HSPCs and augment depletion in the BM prior to HSCT.
Usage: A conjugate with Streptavidin-Saporin and biotinylated CD117 was developed. Mice were conditioned with the conjugate at doses ranging from 0.5 to 1 mg/kg.
We’re highlighting our ZAP antibody internalization kits and our line of secondary antibody saporin conjugates. We have given these products the moniker “ZAP” in place of saporin.
Our ZAP conjugates consist of a variety of secondary antibodies that allow a large number of targeting agents to be screened quickly and cost-efficiently for specificity, functional binding, internalization, and EC50 determination.
The conjugates are constructed using either species-specific secondary antibodies, or streptavidin (for use with biotinylated Targeting Agents), and they are chemically attached to Saporin, a potent plant ribosome-inactivating proteins.
This article by Marquez et al. showcases how our secondary conjugates can be used to screen antibodies and then from that choose the best candidate to create a custom conjugation.
PTGFRN is a cell-surface protein that is upregulated in certain cancer types, including head and neck and, notably, pediatric medulloblastoma, an aggressive cancer with limited therapeutic options. With the selection of the mouse monoclonal antibody 33B7, the authors identified PTGFRN as a potential therapy target, and were able to show that it is internalized by incubation with 33B7.
We’re highlighting our secondary saporin conjugate, Streptavidin-ZAP, which is streptavidinylated saporin. It combines with your biotinylated material to make a targeted toxin.
Unlike a secondary antibody binding to a primary antibody, the bond between streptavidin and biotin is rapid, essentially non-reversible, unaffected by most extremes of pH, organic solvents or denaturing reagents. It is essentially the strongest known noncovalent biological bond between protein and ligand. Streptavidin-ZAP is very modular and works with biotinylated antibodies, peptides, growth factor, aptamers, anything that will recognize a cell surface receptor and can be biotinylated.
This is a publication using a Streptavidin-ZAP reacted with an antibody as the targeting agent.
The authors’ objective was to investigate whether CD206-positive macrophages in the meninges play a role in regulating nociception and pain hypersensitivity. They injected rats intrathecally with conjugate made with biotinylated anti-CD206 reacted with Streptavidin-ZAP and looked at the effects on responses in naïve rats versus ones that received a skin incision, after depletion of CD206+ macrophages.
Their results indicated that depleting CD206+ meningeal macrophages did not regulate basal responses in naïve rats of either sex. However, ablation of these cells after skin injury induced mechanical hypersensitivity in male rats and not in females. Thus, they were able to conclude, that in a sex-dependent manner, CD206-positive meningeal macrophages prevent the spread of pain hypersensitivity after a minor injury.
Babatunde OO, Bibby MG, Atala A, Almeida-Porada G, Porada CD (2026) In utero HSC transplantation for sickle cell disease: A potential therapeutic approach that overcomes complications of current therapies. Prenat Diagn doi: 10.1002/pd.70142 PMID: 41936060
Objective: To examine current evidence and recent advances for treatment of sickle cell disease (SCD).
Summary: Biotinylated anti‐c‐kit/CD117 mAb coupled to a streptavidin‐conjugated saporin has been used to selectively deplete host HSC while preserving the host’s immune system. A single intravenous dose of the anti‐CD45‐saporin ADC enabled > 90% donor (congenic) hematopoietic engraftment and full correction of the SCD phenotype.
Serambeque B, Dias I, Mestre C, Marto CM, Botelho MF, Carvalho MJ, Laranjo M (2026) Photodynamic therapy-based strategies targeted at cancer stem cells: A scoping review. Cancers (Basel) 18(7):1162. doi: 10.3390/cancers18071162 PMID: 41976384
Objective: To examine strategies for targeting cancer stem cells using photodynamic therapy.
Summary: Photochemical internalization (PCI) is a widely adopted approach for targeting surface markers on cancer stem cells. Anti-CD133-SAP was evaluated in colorectal cancer, breast cancer, and melanoma. In CD133high colorectal cancer cells (WiDr), PCI with picomolar concentrations of AC133–saporin completely inhibited viability and colony formation, with no toxicity observed in the absence of light activation. Similar efficacy was observed in CD133+ breast (MDa-MB-231) and CD133high melanoma cells (FMEX-1) but not in CD133− breast cancer cells (MCF7), confirming target specificity. A similar strategy was employed to target CD44 in human cancer cell lines.
