Novel Human Bispecific Aptamer–Antibody Conjugates for Efficient Cancer Cell Killing

Passariello, Margherita; Camorani, Simona; Vetrei, Cinzia; Cerchia, Laura; Lorenzo, Claudia De

doi:10.3390/cancers11091268

Cited by 46 publications

(62 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the basis of the promising results obtained with combined treatments, we also developed a novel bispecific chimeric molecule by chemically linking [39] the anti-EGFR aptamer to ipilimumab mAb. Here we characterized the biological activity of this novel immunoconjugate by testing its effects on tumor cells, on immune cells and on co-cultures of tumor and immune cells.…”

Section: Introductionmentioning

confidence: 99%

Ipilimumab and Its Derived EGFR Aptamer-Based Conjugate Induce Efficient NK Cell Activation against Cancer Cells

Passariello

Camorani

Vetrei

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

The immune checkpoint CTLA-4 (cytotoxic T-lymphocyte-antigen 4), which inhibits the co-stimulatory CD28 signal on T cells, has been recently found expressed on other cell populations, such as tumor and natural killer (NK) cells. We tested for the first time the effects of ipilimumab, the human anti-CTLA4 mAb in clinical use, on these cells and found that it inhibits the growth of tumor cells expressing CTLA-4 also in the absence of lymphocytes, and efficiently activates NK cells, thus suggesting an important unexplored role of NK cells in ipilimumab-modulated immune responses. Interestingly, the epidermal growth factor receptor (EGFR) has been shown to play a key role in tumor cell escape from immune surveillance, and in cytotoxic T lymphocyte inhibition. Thus, we tested combinatorial treatments of ipilimumab with an anti-EGFR aptamer endowed with anti-tumor activity, and constructed for the first time a novel bispecific immunoconjugate, made up of these two compounds. The novel immunoconjugate binds to the target cells, induces the activation of lymphocytes, including NK cells, and inhibits the growth of tumor target cells more efficiently than the parental compounds, by strongly enhancing the cytotoxic activity of both human peripheral blood mononuclear cells and NK cells against tumor cells.

show abstract

Section: Introductionmentioning

confidence: 99%

Ipilimumab and Its Derived EGFR Aptamer-Based Conjugate Induce Efficient NK Cell Activation against Cancer Cells

Passariello

Camorani

Vetrei

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

show abstract

“…Speci cally, Gint4.T is a 2'F-Py RNA aptamer that binds to the extracellular domain of PDGFRβ and inhibits receptor activation and downstream phosphatidyl-3-kinase (PI3K)/Akt and ERK1/2 pathways [22,31,35], thus affecting growth, migration and invasion of mesenchymal TNBC cell lines [31]. On the other side, the high a nity human anti-PD-L1 (10_12) mAb [38,46] not only interferes in the PD-L1/PD-1 interaction but also inhibits the immuneindependent PD-L1 positive TNBC cell growth by affecting the intracellular MAPK pathway [40].…”

Section: Resultsmentioning

confidence: 99%

“…As expected, no effects were observed in the presence of an unrelated IgG antibody and a scrambled aptamer (Scr), used as negative controls. Next, in order to assess whether the aptamer-mediated inhibition of PDGFRβ enhances the inhibitory effects on cell growth exerted by 10_12 mAb in the context of PD-1/PD-L1 interaction between TNBC cells and in ltrating lymphocytes [38,40], we tested the aptamer plus mAb on co-cultures of MDA-MB-231 cells with human lymphocytes by using hPBMCs (effector:target ratio 10:1) ( Fig. 1B-E).…”

Section: Resultsmentioning

confidence: 99%

“…antibody covalently linked to Gint4.T aptamer, thus optimizing the e cacy of the combination therapy by increasing their co-targeting at the tumor site while dispensing lower doses of either single agents and overcoming the limits related to the rapid clearance of the aptamers. We previously developed three different bispeci c conjugates consisting of EGFR aptamer linked to either anti-HER2, anti-PD-L1 or anti-CTLA-4 mAbs [38,39]. By this strategy the advantages of Gint4.T aptamer (nuclease resistance, rapid tumor uptake, durable tumor retention [31] and anti-PD-L1 antibodies (longer half-life in circulation, immunomodulatory activity) could be combined in one single molecule with improved therapeutic effectiveness and pharmacokinetic/pharmacodynamic properties over the parental moieties.…”

Section: Discussionmentioning

confidence: 99%

“…For determination of tumor cell lysis, the release of lactate dehydrogenase (LDH) in the cellular co-culture supernatants was measured by a LDH detection kit (Thermo sher Scienti c, Meridian Rd., Rockoford, IL, USA), as previously described [38,39].…”

Section: Effects Of Combinatorial Treatments On Co-cultures Of Tumor mentioning

confidence: 99%

See 2 more Smart Citations

Aptamer targeted therapy potentiates immune checkpoint blockade in triple-negative breast cancer

Camorani

Passariello

Agnello

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Triple-negative breast cancer (TNBC) is a uniquely aggressive cancer with high rates of relapse due to resistance to chemotherapy. TNBC expresses higher levels of programmed cell death-ligand 1 (PD-L1) compared to other breast cancers, providing the rationale for the recently approved immunotherapy with anti-PD-L1 monoclonal antibodies (mAbs). A huge effort is dedicated to identify actionable biomarkers allowing for combination therapies with immune-checkpoint blockade. Platelet-derived growth factor receptor β (PDGFRβ) is highly expressed in invasive TNBC, both on tumor cells and tumor microenvironment. We recently proved that tumor growth and lung metastases are impaired in mouse models of human TNBC by a high efficacious PDGFRβ aptamer. Hence, we aimed at investigating the effectiveness of a novel combination treatment with the PDGFRβ aptamer and anti-PD-L1 mAbs in TNBC.Methods: The targeting ability of the anti-human PDGFRβ aptamer toward the murine receptor was verified by streptavidin-biotin assays and confocal microscopy, and its inhibitory function by transwell migration assays. The anti-proliferative effects of the PDGFRβ aptamer/anti-PD-L1 mAbs combination was assessed in human MDA-MB-231 and murine 4T1 TNBC cells, both grown as monolayer or co-cultured with lymphocytes. Tumor cell lysis and cytokines secretion by lymphocytes were analyzed by LDH quantification and ELISA, respectively. Orthotopic 4T1 xenografts in syngeneic mice were used for dissecting the effect of aptamer/mAb combination on tumor growth, metastasis and lymphocytes infiltration. Ex vivo analyses through immunohistochemistry, RT-qPCR and immunoblotting were performed. Results: We show that the PDGFRβ aptamer potentiates the anti-proliferative activity of anti-PD-L1 mAbs on both human and murine TNBC cells, according to its human/mouse cross-reactivity. Further, by binding to activated human and mouse lymphocytes, the aptamer enhances the anti-PD-L1 mAb-induced cytotoxicity of lymphocytes against tumor cells. Importantly, the aptamer heightens the antibody efficacy in inhibiting tumor growth and lung metastases in mice. It acts on both tumor cells, inhibiting Akt and ERK1/2 signaling pathways, and immune populations, increasing intratumoral CD8+T cells and reducing FOXP3+Treg cells. Conclusion: Co-treatment of PDGFRβ aptamer with anti-PD-L1 mAbs is a viable strategy, thus providing for the first an evidence of the efficacy of PDGFRβ/PD-L1 co-targeting combination therapy in TNBC.

show abstract

CAR‐Aptamers Enable Traceless Enrichment and Monitoring of CAR‐Positive Cells and Overcome Tumor Immune Escape

Zhou,

Abudureheman,

Zheng

et al. 2023

Advanced Science

View full text Add to dashboard Cite

Chimeric antigen receptor (CAR)‐positive cell therapy, specifically with anti‐CD19 CAR‐T (CAR19‐T) cells, achieves a high complete response during tumor treatment for hematological malignancies. Large‐scale production and application of CAR‐T therapy can be achieved by developing efficient and low‐cost enrichment methods for CAR‐T cells, expansion monitoring in vivo, and overcoming tumor escape. Here, novel CAR‐specific binding aptamers (CAR‐ap) to traceless sort CAR‐positive cells and obtain a high positive rate of CAR19‐T cells is identified. Additionally, CAR‐ap‐enriched CAR19‐T cells exhibit similar antitumor capacity as CAR‐ab (anti‐CAR antibody)‐enriched CAR‐T cells. Moreover, CAR‐ap accurately monitors the expansion of CAR19‐T cells in vivo and predicts the prognosis of CAR‐T treatment. Essentially, a novel class of stable CAR‐ap‐based bispecific circular aptamers (CAR‐bc‐ap) is constructed by linking CAR‐ap with a tumor surface antigen (TSA): protein tyrosine kinase 7 (PTK7) binding aptamer Sgc8. These CAR‐bc‐aps significantly enhance antitumor cytotoxicity with a loss of target antigens by retargeting CAR‐T cells to the tumor in vitro and in vivo. Overall, novel CAR‐aptamers are screened for traceless enrichment, monitoring of CAR‐positive cells, and overcoming tumor cell immune escape. This provides a low‐cost and high‐throughput approach for CAR‐positive cell‐based immunotherapy.

show abstract

Novel Human Bispecific Aptamer–Antibody Conjugates for Efficient Cancer Cell Killing

Cited by 46 publications

References 71 publications

Ipilimumab and Its Derived EGFR Aptamer-Based Conjugate Induce Efficient NK Cell Activation against Cancer Cells

Ipilimumab and Its Derived EGFR Aptamer-Based Conjugate Induce Efficient NK Cell Activation against Cancer Cells

Aptamer targeted therapy potentiates immune checkpoint blockade in triple-negative breast cancer

CAR‐Aptamers Enable Traceless Enrichment and Monitoring of CAR‐Positive Cells and Overcome Tumor Immune Escape

Contact Info

Product

Resources

About