Antibody-Based Approaches to Target Pancreatic Tumours

Sorbara, Marie; Cordelier, Pierre; Béry, Nicolas

doi:10.3390/antib11030047

Cited by 8 publications

(9 citation statements)

References 149 publications

(170 reference statements)

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“…Although a benefit of this unintended effect may be the untargeted destruction of tumor-associated support cells and tumor-suppressive immune cells that populate the environment. In addition, due to the dense, desmoplastic stroma of the PDAC TME, limitations in efficacy may derive from regulations in antibody drugs properly reaching most cancer cells ( 189 ). New clinical trials are investigating a combination of treatments along with ADCs to maximize their therapeutic efficacy.…”

Section: Novel Therapeutic Strategiesmentioning

confidence: 99%

Pancreatic cancer tumor microenvironment is a major therapeutic barrier and target

Hartupee,

Nagalo,

Chabu

et al. 2024

Front. Immunol.

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Pancreatic Ductal Adenocarcinoma (PDAC) is projected to become the 2nd leading cause of cancer-related deaths in the United States. Limitations in early detection and treatment barriers contribute to the lack of substantial success in the treatment of this challenging-to-treat malignancy. Desmoplasia is the hallmark of PDAC microenvironment that creates a physical and immunologic barrier. Stromal support cells and immunomodulatory cells face aberrant signaling by pancreatic cancer cells that shifts the complex balance of proper repair mechanisms into a state of dysregulation. The product of this dysregulation is the desmoplastic environment that encases the malignant cells leading to a dense, hypoxic environment that promotes further tumorigenesis, provides innate systemic resistance, and suppresses anti-tumor immune invasion. This desmoplastic environment combined with the immunoregulatory events that allow it to persist serve as the primary focus of this review. The physical barrier and immune counterbalance in the tumor microenvironment (TME) make PDAC an immunologically cold tumor. To convert PDAC into an immunologically hot tumor, tumor microenvironment could be considered alongside the tumor cells. We discuss the complex network of microenvironment molecular and cellular composition and explore how they can be targeted to overcome immuno-therapeutic challenges.

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Section: Novel Therapeutic Strategiesmentioning

confidence: 99%

Pancreatic cancer tumor microenvironment is a major therapeutic barrier and target

Hartupee,

Nagalo,

Chabu

et al. 2024

Front. Immunol.

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“…In addition to full-length antibodies, smaller antibody fragments such as fragment antigen binding (Fab), single-chain fragment variable (scFv), and single-domain antibodies are used in drug delivery. The smaller fragments are easier to produce and can potentially penetrate tissues more effectively than full-length antibodies [ 196 , 199 , 200 ]. To prepare ADCs, antibodies are conjugated to cytotoxic drugs via a suitable linker ( Figure 6 b) [ 197 , 198 ].…”

Section: Drug-conjugate Delivery Systems In Pancreatic Cancer Treatmentmentioning

confidence: 99%

“…The failure of the antibody–drug conjugates in pancreatic adenocarcinoma may be attributed to desmoplasia, which significantly impedes the access of antibody–drug conjugates to pancreatic tumor cells as a consequence of their large molecular size [ 58 ]. In addition, pancreatic adenocarcinoma exhibits heterogeneity in the expression of antigens, not only across different patients but also within the same patient over time, which may contribute to treatment failure [ 200 , 205 ]. Therefore, it is recommended that smaller antibody fragments be used, such as the single-chain fragment variable, and single-domain antibodies for the development of ADCs for pancreatic cancer therapy [ 36 , 205 ].…”

Section: Drug-conjugate Delivery Systems In Pancreatic Cancer Treatmentmentioning

confidence: 99%

Drug Delivery Strategies for the Treatment of Pancreatic Cancer

et al. 2023

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Pancreatic cancer is fast becoming a global menace and it is projected to be the second leading cause of cancer-related death by 2030. Pancreatic adenocarcinomas, which develop in the pancreas’ exocrine region, are the predominant type of pancreatic cancer, representing about 95% of total pancreatic tumors. The malignancy progresses asymptomatically, making early diagnosis difficult. It is characterized by excessive production of fibrotic stroma known as desmoplasia, which aids tumor growth and metastatic spread by remodeling the extracellular matrix and releasing tumor growth factors. For decades, immense efforts have been harnessed toward developing more effective drug delivery systems for pancreatic cancer treatment leveraging nanotechnology, immunotherapy, drug conjugates, and combinations of these approaches. However, despite the reported preclinical success of these approaches, no substantial progress has been made clinically and the prognosis for pancreatic cancer is worsening. This review provides insights into challenges associated with the delivery of therapeutics for pancreatic cancer treatment and discusses drug delivery strategies to minimize adverse effects associated with current chemotherapy options and to improve the efficiency of drug treatment.

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“…We chose to produce an ARC to address the unmet need for accurate diagnosis and effective therapeutics for pancreatic cancer, which has a dismally low 5 year survival rate of only 11% . Less than 20% of patients have tumors confined within the pancreas that can be surgically removed, but most of these patients will relapse in 2–3 years after surgery . More than 80% of patients have inoperable/unresectable cancer, as the tumors have reached the surrounding blood vessels or metastasized.…”

Section: Introductionmentioning

confidence: 99%

Site-specific Conjugation of 6 DOTA Chelators to a CA19-9-targeting scFv-Fc Antibody for Imaging and Therapy

Chen¹,

Yu²,

Tian³

et al. 2023

J. Med. Chem.

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Antibodies conjugated with diagnostic/therapeutic radionuclides are attractive options for inoperable cancers lacking accurate imaging methods and effective therapeutics, such as pancreatic cancer. Hence, we have produced an antibody radionuclide conjugate termed TE-1132 comprising a α-CA19-9 scFv-Fc that is site-specifically conjugated at each C-terminus to 3 DOTA chelators via a cysteine-containing peptide linker. The smaller scFv-Fc size facilitates diffusivity within solid tumors, whereas the chelator-to-antibody ratio of six enabled 177 Luradiolabeled TE-1132 to exhibit high radioactivity up to 520 MBq/nmol. In mice bearing BxPC3 tumors, immuno-SPECT/CT imaging of [ 111 In]In-TE-1132 and the biodistribution of [ 177 Lu]Lu-TE-1132 showed selective tumor accumulation. Single and multiple doses of [ 177 Lu]Lu-TE-1132 effectively inhibited the BxPC3 tumor growth and prolonged the survival of mice with no irreversible body weight loss or hematopoietic damage. The adequate pharmacokinetic parameters, prominent tumor accumulation, and efficacy with good safety in mice encourage the further investigation of theranostic TE-1132 for treating pancreatic cancer.

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Antibody-Based Approaches to Target Pancreatic Tumours

Cited by 8 publications

References 149 publications

Pancreatic cancer tumor microenvironment is a major therapeutic barrier and target

Pancreatic cancer tumor microenvironment is a major therapeutic barrier and target

Drug Delivery Strategies for the Treatment of Pancreatic Cancer

Site-specific Conjugation of 6 DOTA Chelators to a CA19-9-targeting scFv-Fc Antibody for Imaging and Therapy

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