Optimal design, anti-tumour efficacy and tolerability of anti-CXCR4 antibody drug conjugates

Scientific Reports
Maria José CostaShu-Hui Liu

Abstract

Antibody-drug conjugates (ADCs) are promising therapies for haematological cancers. Historically, their therapeutic benefit is due to ADC targeting of lineage-restricted antigens. The C-X-C motif chemokine receptor 4 (CXCR4) is attractive for targeted therapy of haematological cancers, given its expression in multiple tumour types and role in cancer "homing" to bone marrow. However, CXCR4 is also expressed in haematopoietic cells and other normal tissues, raising safety challenges to the development of anti-CXCR4 ADCs for cancer treatment. Here, we designed the first anti-CXCR4 ADC with favourable therapeutic index, effective in xenografts of haematopoietic cancers resistant to standard of care and anti-CXCR4 antibodies. We screened multiple ADC configurations, by varying type of linker-payload, drug-to-antibody ratio (DAR), affinity and Fc format. The optimal ADC bears a non-cleavable linker, auristatin as payload at DAR = 4 and a low affinity antibody with effector-reduced Fc. Contrary to other drugs targeting CXCR4, anti-CXCR4 ADCs effectively eliminated cancer cells as monotherapy, while minimizing leucocytosis. The optimal ADC selectively eliminated CXCR4+ cancer cells in solid tumours, but showed limited toxicity to norma...Continue Reading

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Citations

Oct 6, 2020·Frontiers in Oncology·Daniel CancillaJohn F DiPersio
Jun 4, 2020·Scientific Reports·Melak WeldenegodguadJuha Kantanen
Dec 9, 2020·Chemical Society Reviews·Stephen J WalshDavid R Spring

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Methods Mentioned

BETA
xenografts
xenograft
glycosylation
Flow cytometry
Surface
biosensor
chip
Assay

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FlowJo
GraphPad Prism
ChemInnovation
SoftMaxPro
Phoenix WinNonlin7
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Biacore T200 Evaluation
IncuCyte
HisTrap Excel

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