Multifunctional Glycoconjugates for Recruiting Natural Antibodies against Cancer Cells

Liet, Benjamin; Laigre, Eugénie; Goyard, David; Todaro, Biagio; Tiertant, Claire; Boturyn, Didier; Berthet, Nathalie; Renaudet, Olivier

doi:10.1002/chem.201904616

Cited by 3 publications

(6 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[ 34 ] Recently, we and others have found that a linear (polydisperse) polymeric scaffold (Figure 1A), obtained by radical polymerization, substituted with multiple dinitrophenyl hapten copies increased the avidity of the complex formation with anti‐dinitrophenyl antibodies. [ 18,20–22,35 ]…”

Section: Introductionmentioning

confidence: 99%

“…[ 26 ] Cell surface recruitment of endogenous antibodies by synthetic small molecules comprising a cell surface protein‐ligand is also gaining great interest. [ 21,27–30 ] However, like mAb drugs, they require the expression of a specific antigen signature on the cell surface.…”

Section: Introductionmentioning

confidence: 99%

“…[ 8,14–16 ] Several of these strategies rely on multivalent presentation of hapten motifs to enhance the avidity of the antibody complexation on the cancer cell surface. [ 15,17–22 ] Achieving the latter without the need for a specific receptor being overexpressed on target cancer cells, would be of tremendous therapeutic benefit. Recently, we and others have explored this domain by designing chimeric molecules that comprise a lipid anchor, binding to the external phospholipid cellular membrane, and a hapten motif, that recruits anti‐hapten antibodies to the cell surface ( Figure A).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Hapten/Myristoyl Functionalized Poly(propyleneimine) Dendrimers as Potent Cell Surface Recruiters of Antibodies for Mediating Innate Immune Killing

et al. 2023

View full text Add to dashboard Cite

Recruiting endogenous antibodies to the surface of cancer cells using antibody‐recruiting molecules has the potential to unleash innate immune effector killing mechanisms against antibody‐bound cancer cells. However, the affinity of endogenous antibodies is relatively low, and many currently explored antibody‐recruiting strategies rely on targeting over‐expressed receptors, which have not yet been identified in most solid tumors. In this study, we aimed to address both challenges by functionalizing poly(propyleneimine) (PPI) dendrimers with both multiple dinitrophenyl (DNP) motifs, as anti‐hapten antibody‐recruiting motifs, and myristoyl motifs, as universal phospholipid cell membrane anchoring motifs, to recruit anti‐hapten antibodies to cell surfaces. By exploiting the multivalency of the ligand exposure on the dendrimer scaffold, we demonstrated that dendrimers featuring ten myristoyl and six DNP motifs exhibited the highest antibody‐recruiting capacity in vitro. Furthermore, we showed that treating cancer cells with these dendrimers in vitro marked them for phagocytosis by macrophages in the presence of anti‐hapten antibodies. As a proof‐of‐concept, we showed that intratumoral injection of these dendrimers in vivo in tumor‐bearing mice, resulted in the recruitment of anti‐DNP antibodies to the surface of cells in the tumor microenvironment. Our findings highlight the potential of dendrimers as a promising class of novel antibody‐recruiting molecules for use in cancer immunotherapy.This article is protected by copyright. All rights reserved

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Hapten/Myristoyl Functionalized Poly(propyleneimine) Dendrimers as Potent Cell Surface Recruiters of Antibodies for Mediating Innate Immune Killing

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Here a synthetic scaffold is equipped with both a tumor binding domain (TBD) and a multivalent array of rhamnose sugars, serving as an antibody binding domain (ABD). For example, Coen et al used a rhamnose-decorated polymer lipid anchored into cells, while Liet et al demonstrated that dendrimeric rhamnose conjugates can bridge antirhamnose antibodies with target cells. , Alternatively, Sheridan et al, Jakobsche et al, and Goyard et al. demonstrated antirhamnose-induced CDC of target cells through artificial multivalent rhamnose arrays on target cells (via lipid-anchored rhamnose, rhamnose-NHS-mediated cell surface labeling, or metabolic labeling to incorporate dendrimeric rhamnose, respectively). − Interestingly, Li et al used rhamnose- and folic acid-functionalized liposomes to induce targeted CDC in vitro and tumor regression in vivo …”

Section: Introductionmentioning

confidence: 99%

Offsetting Low-Affinity Carbohydrate Binding with Covalency to Engage Sugar-Specific Proteins for Tumor-Immune Proximity Induction

Lake,

Rullo

2023

ACS Cent. Sci.

View full text Add to dashboard Cite

Carbohydrate-binding receptors are often used by the innate immune system to potentiate inflammation, target endocytosis/destruction, and adaptive immunity (e.g., CD206, DC-SIGN, MBL, and anticarbohydrate antibodies). To access this class of receptors for cancer immunotherapy, a growing repertoire of bifunctional proximity-inducing therapeutics use high-avidity multivalent carbohydrate binding domains to offset the intrinsically low affinity associated with monomeric carbohydrate−protein binding interactions (K d ≈ 10 −3 −10 −6 M). For applications aimed at recruiting anticarbohydrate antibodies to tumor cells, large synthetic scaffolds are used that contain both a tumor-binding domain (TBD) and a multivalent antibody-binding domain (ABD) comprising multiple L-rhamnose monosaccharides. This allows for stable bridging between tumor cells and antibodies, which activates tumoricidal immune function. Problematically, such multivalent macromolecules can face limitations including synthetic and/or structural complexity and the potential for off-target immune engagement. We envisioned that small bifunctional "proximity-inducing" molecules containing a low-affinity monovalent ABD could efficiently engage carbohydrate-binding receptors for tumor-immune proximity by coupling weak binding with covalent engagement. Typical covalent drugs and electrophilic chimeras use high-affinity ligands to promote the fast covalent engagement of target proteins (i.e., large k inact /K I ), driven by a favorably small K I for binding. We hypothesized the much less favorable K I associated with carbohydrate−protein binding interactions can be offset by a favorably large k inact for the covalent labeling step. In the current study, we test this hypothesis in the context of a model system that uses rhamnose-specific antibodies to induce tumor-immune proximity and tumoricidal function. We discovered that synthetic chimeric molecules capable of preorganizing an optimal electrophile (i.e., SuFEx vs activated ester) for protein engagement can rapidly covalently engage natural sources of antirhamnose antibody using only a single low-affinity rhamnose monosaccharide ABD. Strikingly, we observe chimeric molecules lacking an electrophile, which can only noncovalently bind the antibody, completely lack tumoricidal function. This is in stark contrast to previous work targeting small molecule hapten and peptide-specific antibodies. Our findings underscore the utility of covalency as a strategy to engage low-affinity carbohydrate-specific proteins for tumor-immune proximity induction.

show abstract

“…4 The cyclo-RGD-Rha conjugate with clustering Rha was recently designed and studied. 5 It was proved that the multivalent presentation of Rha haptens with cluster avidity could efficiently enhance the antibody recruitment and mediate stronger cytotoxicity against cancer cells. Similarly, multivalent display of TBT could also effectively improve the affinity for ARMs to target cancer cells with a low antigen density.…”

mentioning

confidence: 99%

CD44 and EGFR Dual-Targeted Antibody-Recruiting Complex Based on Hyaluronic Acid Grafted with β-Cyclodextrin and Multivalent Rhamnose for Cancer Immunotherapy

Zheng¹,

Li²,

Lin³

et al. 2023

Synthesis

View full text Add to dashboard Cite

A new generation of multivalent antibody-recruiting molecules (ARMs) with dual-targeting tumor-binding termini (TBT), including hyaluronic acid targeting CD44 and nanobody 7D12 or peptide GE11 targeting EGFR, was constructed for cancer immunotherapy. The 7D12 or GE11 were assembled onto β-cyclodextrin-grafted hyaluronic acid (HACD) with multivalent rhamnose via host-guest interaction to form macromolecule complexes. The immunological studies proved that these complexes had dual-targetability on CD44 and EGFR and the rhamnose on HACD could recruit anti-Rha antibodies to mediate cytotoxicity against the targeted tumor cells. This bispecific ARM strategy provides a platform for cancer immunotherapy.

show abstract

Multifunctional Glycoconjugates for Recruiting Natural Antibodies against Cancer Cells

Cited by 3 publications

References 25 publications

Hapten/Myristoyl Functionalized Poly(propyleneimine) Dendrimers as Potent Cell Surface Recruiters of Antibodies for Mediating Innate Immune Killing

Hapten/Myristoyl Functionalized Poly(propyleneimine) Dendrimers as Potent Cell Surface Recruiters of Antibodies for Mediating Innate Immune Killing

Offsetting Low-Affinity Carbohydrate Binding with Covalency to Engage Sugar-Specific Proteins for Tumor-Immune Proximity Induction

CD44 and EGFR Dual-Targeted Antibody-Recruiting Complex Based on Hyaluronic Acid Grafted with β-Cyclodextrin and Multivalent Rhamnose for Cancer Immunotherapy

Contact Info

Product

Resources

About