Engineering a high-affinity humanized anti-CD24 antibody to target hepatocellular carcinoma by a novel CDR grafting design

Sun, Fumou; Wang, Tong; Jiang, Jiahao; Wang, Yan; Ma, Zhaoxiong; Li, Zhaoting; Han, Yue; Pan, Mingzhu; Cai, Jialing; Wang, Min; Zhang, Juan

doi:10.18632/oncotarget.17228

Cited by 31 publications

(18 citation statements)

References 46 publications

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“…Despite the low potency of doxorubicin (the IC50 is in the low micromolar range) compared to the active drugs in most ADCs, the ADC was still able to suppress tumour growth, decrease systemic toxicity, and prolong the survival of HCC-bearing nude mice [ 108 ]. A positive outcome for another ADC targeting CD24 has also been reported; the active drug was the previously discussed, more potent microtubule inhibitor, monomethyl auristatin E [ 109 ].…”

Section: Hepatocellular Carcinomamentioning

confidence: 99%

Antibody-Drug Conjugates and Targeted Treatment Strategies for Hepatocellular Carcinoma: A Drug-Delivery Perspective

Dahlgren

Lennernäs

2020

Molecules

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Increased understanding of cancer biology, pharmacology and drug delivery has provided a new framework for drug discovery and product development that relies on the unique expression of specific macromolecules (i.e., antigens) on the surface of tumour cells. This has enabled the development of anti-cancer treatments that combine the selectivity of antibodies with the efficacy of highly potent chemotherapeutic small molecules, called antibody-drug conjugates (ADCs). ADCs are composed of a cytotoxic drug covalently linked to an antibody which then selectively binds to a highly expressed antigen on a cancer cell; the conjugate is then internalized by the cell where it releases the potent cytotoxic drug and efficiently kills the tumour cell. There are, however, many challenges in the development of ADCs, mainly around optimizing the therapeutic/safety benefits. These challenges are discussed in this review; they include issues with the plasma stability and half-life of the ADC, its transport from blood into and distribution throughout the tumour compartment, cancer cell antigen expression and the ADC binding affinity to the target antigen, the cell internalization process, cleaving of the cytotoxic drug from the ADC, and the cytotoxic effect of the drug on the target cells. Finally, we present a summary of some of the experimental ADC strategies used in the treatment of hepatocellular carcinoma, from the recent literature.

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Section: Hepatocellular Carcinomamentioning

confidence: 99%

Antibody-Drug Conjugates and Targeted Treatment Strategies for Hepatocellular Carcinoma: A Drug-Delivery Perspective

Dahlgren

Lennernäs

2020

Molecules

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“…By contrast, in patient-derived ovarian tumor samples, CD24-negative cells were more aggressive than CD24-positive cells, with stemness features and resistance to carboplatin and paclitaxel [172]. In hepatocellular carcinoma derived-xenografts, using a humanized monoclonal anti-CD24 antibody had anti-tumor effects, while there was no data on the eradication of the pool of cancer stem cells [173].…”

Section: Targeting Cancer Stem Cell Surface Markersmentioning

confidence: 99%

Targeting Cancer Stem Cells to Overcome Chemoresistance

Nunes

Hamdan

Lebœuf

et al. 2018

IJMS

127

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Cancers are heterogeneous at the cell level, and the mechanisms leading to cancer heterogeneity could be clonal evolution or cancer stem cells. Cancer stem cells are resistant to most anti-cancer treatments and could be preferential targets to reverse this resistance, either targeting stemness pathways or cancer stem cell surface markers. Gold nanoparticles have emerged as innovative tools, particularly for photo-thermal therapy since they can be excited by laser to induce hyperthermia. Gold nanoparticles can be functionalized with antibodies to specifically target cancer stem cells. Preclinical studies using photo-thermal therapy have demonstrated the feasibility of targeting chemo-resistant cancer cells to reverse clinical chemoresistance. Here, we review the data linking cancer stem cells and chemoresistance and discuss the way to target them to reverse resistance. We particularly focus on the use of functionalized gold nanoparticles in the treatment of chemo-resistant metastatic cancers.

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“…Subsequent studies identified specific antigen binding regions within the variable domains of the antibody called complementarity determining regions (CDRs). This development led to the ability to further reduce the immunogenicity of rodent‐derived antibodies by grafting only the CDRs and replacing the remaining framework regions (Fr) with the most homologous human sequences, resulting in the generation of humanized antibodies (Agadjanyan et al, ; Lo, ; Sun et al, ). It is generally recognized that even fully human mAbs can initiate a clinically relevant anti‐drug antibody response through the activation of CD4 + T cells and B cells (Baker & Jones, ; Harding, Stickler, Razo, & DuBridge, ).…”

Section: Introductionmentioning

confidence: 99%

Validation of a de‐immunization strategy for monoclonal antibodies using cynomolgus macaque as a surrogate for human

Kovalova

Boyles

Wen

et al. 2020

Biopharm & Drug Disp

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The immunogenicity of biotherapeutics presents a major challenge during the clinical development of new protein drugs including monoclonal antibodies. To address this, multiple humanization and de-immunization techniques that employ in silico algorithms and in vitro test systems have been proposed and implemented. However, the success of these approaches has been variable and to date, the ability of these techniques to predict immunogenicity has not been systematically tested in humans or other primates. This study tested whether antibody humanization and deimmunization strategies reduce the risk of anti-drug antibody (ADA) development using cynomolgus macaque as a surrogate for human. First human-cyno chimeric antibodies were constructed by grafting the variable domains of the adalimumab and golimumab monoclonal antibodies onto cynomolgus macaque IgG1 and Igκ constant domains followed by framework germlining to cyno to reduce the xenogenic content.Next, B and T cell epitopes and aggregation-prone regions were identified using common in silico methods to select domains with an ADA risk for additional modification. The resultant engineered antibodies had a comparable affinity for TNFα, demonstrated similar biophysical properties, and exhibited significantly reduced ADA levels in cynomolgus macaque compared with the parental antibodies, with a corresponding improvement in the pharmacokinetic profile. Notably, plasma concentrations of the engineered antibodies were quantifiable through 504 hours (chimeric) and 840 hours (germlined/de-immunized), compared with only 336 hours (adalimumab) or 336-672 hours (golimumab). The results point to the significant value in the investment in these engineering strategies as an important guide for monoclonal antibody optimization that can contribute to improved clinical outcomes.

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Engineering a high-affinity humanized anti-CD24 antibody to target hepatocellular carcinoma by a novel CDR grafting design

Cited by 31 publications

References 46 publications

Antibody-Drug Conjugates and Targeted Treatment Strategies for Hepatocellular Carcinoma: A Drug-Delivery Perspective

Antibody-Drug Conjugates and Targeted Treatment Strategies for Hepatocellular Carcinoma: A Drug-Delivery Perspective

Targeting Cancer Stem Cells to Overcome Chemoresistance

Validation of a de‐immunization strategy for monoclonal antibodies using cynomolgus macaque as a surrogate for human

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