ArticleJournal for immunotherapy of cancer2021
Generation of a safe and efficacious llama single-domain antibody fragment (vHH) targeting the membrane-proximal region of 4-1BB for engineering therapeutic bispecific antibodies for cancer.
Article in Journal for immunotherapy of cancer, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 43 citations in OpenAlex.
- Review
- A simple and broadly applicable nanobody-based approach to generate potent TNFR agonists.Cell death & disease · 2026Article
- Tiny tools closing the gap: nanobodies in research and therapy.Function (Oxford, England) · 2026Review
- An iterative strategy to design 4-1BB agonist nanobodies de novo with generative AI models.Scientific reports · 2025Article
- Nanobodies and their derivatives: pioneering the future of cancer immunotherapy.Cell communication and signaling : CCS · 2025Review
- Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody, combined with PD-1 blockade potentiates antitumor immunity via complementary immune modulatory effects.Journal for immunotherapy of cancer · 2025Article
- Nanobodies targeting the tumor microenvironment and their formulation as nanomedicines.Molecular cancer · 2025Review
- Safety Assessment of Camelid-Derived Single-Domain Antibody as Feed Additive for Juvenile Whiteleg Shrimp (Animals : an open access journal from MDPI · 2024Article
- Characterization of a Trispecific PD-L1 Blocking Antibody That Exhibits EGFR-Conditional 4-1BB Agonist Activity.Antibodies (Basel, Switzerland) · 2024Article
- The enhanced antitumor activity of bispecific antibody targeting PD-1/PD-L1 signaling.Cell communication and signaling : CCS · 2024Review
- i-shaped antibody engineering enables conformational tuning of biotherapeutic receptor agonists.Nature communications · 2024Article
- Anti-PD-L1-Based Bispecific Antibodies Targeting Co-Inhibitory and Co-Stimulatory Molecules for Cancer Immunotherapy.Molecules (Basel, Switzerland) · 2024Review
- Review
- Small Antibodies with Big Applications: Nanobody-Based Cancer Diagnostics and Therapeutics.Cancers · 2023Review
- A bispecific antibody AP203 targeting PD-L1 and CD137 exerts potent antitumor activity without toxicity.Journal of translational medicine · 2023Article
- Nanobodies in cell-mediated immunotherapy: On the road to fight cancer.Frontiers in immunology · 2023Review
- Design and selection of anti-PD-L1 single-domain antibody and tumor necrosis factor superfamily ligands for an optimal vectorization in an oncolytic virus.Frontiers in bioengineering and biotechnology · 2023Article
- Single domain Camelid antibody fragments for molecular imaging and therapy of cancer.Frontiers in oncology · 2023Review
- RASGRP2 is a potential immune-related biomarker and regulates mitochondrial-dependent apoptosis in lung adenocarcinoma.Frontiers in immunology · 2023Article
- Development of therapeutic antibodies for the treatment of diseases.Molecular biomedicine · 2022Review
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Authors and funding
19 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe discovery of checkpoint inhibitors towards cytotoxic T-lymphocyte protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) has been revolutionary for the treatment of cancers. These therapies have only offered an average of 20%-30% response rates across the tumor spectrum and the combination of agonists towards the tumor-necrosis superfamily members, such as 4-1BB and CD40, has shown potent efficacy in preclinical studies; however, these agonists have exhibited high degrees of toxicity with limited efficacy in human trials. In this study, we have generated a single-domain antibody towards a unique epitope of 4-1BB that limits its potential on-target toxicity while maintaining sufficient potency. This 4-1BB binder is ideal for use in the engineering of multispecific antibodies to localize 4-1BB activation within the tumor microenvironment, as shown here by a anti-PD-L1/4-1BB bispecific candidate (PM1003).
methodsTo determine the functional activity of the 4-1BB- and PD-L1-binding elements of PM1003,
resultsPM1003 shows potent activation of 4-1BB and blockade of PD-L1 in cell-based assays. 4-1BB activation was exerted through the bridging of PD-L1 on target cells and 4-1BB on effector cells. No PD-L1-independent activation of 4-1BB was observed. Through X-ray crystallography, a unique binding epitope in the cysteine-rich domain 4 (CRD4) region was resolved that provides high potency and potentially low on-target toxicity as determined by primary immune cell assays and toxicity evaluation
conclusionsA unique single-domain antibody was discovered that binds to the CRD4 domain of 4-1BB. When incorporated into a 4-1BB/PD-L1 bispecific (PM1003), we have shown the potent inhibition of PD-L1 activity with 4-1BB agonism upon cross-bridging with PD-L1
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