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?? Upcoming Webinar! AbDrop?: Accelerating Your Antibody Discovery with Single B Solution?
Biointron is excited to announce our upcoming webinar in collaboration with the Antibody Society, which will explore how AbDrop?, our advanced single B cell screening platform, is revolutionizing antibody discovery.?
??? Listen to Episode 2 of Biointron’s Spotlight on Antibodies, a monthly podcast diving deep into the world of antibody innovation. This February, top news includes novel antibodies to treat obesity, hereditary angioedema, and B cells. Find us wherever you listen to podcasts!
In our latest episode of the new Antibody ABCs video series, we define computational antibody design. Watch the playlist here.
This Week’s News?
Trends – Antibody-Toxin Conjugates?
Antibody-toxin conjugates (ATCs) are targeted therapeutic agents that combine an antibody with a potent toxin to selectively eliminate diseased cells, such as cancer cells or infected cells. These conjugates leverage the antibody’s specificity to deliver the toxin directly to target cells, minimizing off-target effects and systemic toxicity. ATCs may use bacterial or plant-derived toxins, such as Pseudomonas exotoxin or ricin, which disrupt essential cellular processes upon internalization. Immunotoxins are antibody-toxin conjugates designed to selectively bind surface antigens on tumor cells and deliver potent cytotoxic effects after internalization. These therapeutics have shown promising efficacy and have received FDA approval for treating various hematological malignancies, including hairy cell leukemia and cutaneous T-cell lymphoma.?
This week, a study was published led by researchers from The University of Texas MD Anderson Cancer Center that describes an ATC targeting CD47 linked to the bacterial toxin listeriolysin O for cancer immunotherapy. Antigen-presenting cells (APCs) capture tumor cells and present tumor-derived antigens to trigger immune responses. However, this process is hindered by checkpoints in phagocytosis and inefficient transport of antigenic peptides from phagolysosomes to the cytosol. This ATC targets the "don't eat me" signal, CD47, and links it to the bacterial toxin listeriolysin O (LLO) from Listeria monocytogenes via a cleavable linker (CD47–LLO). CD47–LLO helps macrophages engulf cancer cells, and once internalized, LLO is released and activates pore formation in the phagolysosomal membrane. This enhances the presentation of tumor-derived peptides and activates immune sensors in the cytosol, suggesting that designing ATCs to boost immune recognition of tumors could be a promising approach for treating various cancers.
Likewise, researchers from University of Colorado Anschutz Medical Campus developed a diphtheria toxin-based bivalent anti-human CD47 immunotoxin (bi-CD47-IT) for targeting CD47+ cancers, including T-cell acute lymphoblastic leukemia (T-ALL). Using a DT-resistant Pichia pastoris expression system, bi-CD47-IT showed strong efficacy in T-ALL cell line-derived (CDX) and patient-derived (PDX) xenograft mouse models, significantly prolonging survival and effectively depleting T-ALL blast cells in multiple organs. In a Molt-4 CDX model, bi-CD47-IT cured 60% of tumor-bearing mice. Despite CD47’s presence on normal tissues, bi-CD47-IT did not bind to red blood cells or cause hemagglutination. In humanized mice, it transiently depleted lymphocytes for about four weeks without adverse effects. With its selective tumor targeting and favorable safety profile, bi-CD47-IT represents a promising therapeutic candidate for CD47+ cancers.?
Meanwhile in the research space, scientists have found that conditionally activated immunotoxins with prolonged half-life can enhance the anti-tumor activity. Since challenges such as short half-life and toxicity to healthy tissues limit broader application of immunotoxins, a team?developed a tumor-conditional immunotoxin called NbHSA-uPA-A1-PE24. This design incorporates an anti-HSA nanobody (NbHSA) fused to A1-PE24, an immunotoxin targeting mesothelin, via a linker cleavable by the tumor-associated protease urokinase-type plasminogen activator (uPA). NbHSA binds to human serum albumin (HSA) in circulation, extending the immunotoxin’s half-life and creating a spatial barrier between A1 and mesothelin to reduce toxicity in healthy tissues. The uPA-cleavable linker ensures that activation occurs specifically within the tumor microenvironment. In animal studies, NbHSA-uPA-A1-PE24 demonstrated significantly improved half-life, enhanced tumor accumulation, and potent anti-tumor effects in pancreatic and gastric cancer models. These findings highlight the potential of this strategy to improve the safety and efficacy of immunotoxins, offering new directions for cancer treatment development.
Besides half-life, another factor that can improve the cytotoxicity of immunotoxins is reducing the affinity of the antibody in acidic pH. This study investigated how antibody properties affect immunotoxin efficacy by comparing two anti-GPC3 antibodies, 32A9 and 42A1, in scFv-mPE24 immunotoxins. Despite similar antigen binding and internalization rates, 32A9 scFv-mPE24 demonstrated superior antitumor activity due to faster degradation in lysosomes and more efficient toxin release. The key difference was 32A9’s sensitivity to acidic pH, which led to antigen dissociation and degradation, enhancing cytotoxicity, whereas 42A1 remained stable in lysosomes, delaying toxin release. These findings suggest that incorporating low pH-sensitive antibodies could improve the design of immunotoxins and other lysosome-dependent antibody-drug conjugates.
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