Advances in immunotoxin engineering: precision therapeutic strategies in modern oncology

Medical Oncology, Journal Year: 2024, Volume and Issue: 41(10)

Published: Sept. 4, 2024

Language: Английский

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Technical, Preclinical, and Clinical Developments of Fc Glycan-Specific Antibody-drug Conjugates

RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 18, 2024

Fc-glycan-specific ADC is a significant advance in site-specific ADCs for cancer therapy. Notably, JSKN003 and IBI343 have demonstrated promising results phase 1 clinical trials are advancing into 3 studies.

Language: Английский

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Towards Aptamer-Targeted Drug Delivery to Brain Tumors: The Synthesis of Ramified Conjugates of an EGFR-Specific Aptamer with MMAE on a Cathepsin B-Cleavable Linker

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(11), P. 1434 - 1434

Published: Nov. 11, 2024

Targeted delivery of chemotherapeutic agents is a well-established approach to cancer therapy. Antibody-drug conjugates (ADCs) typically carry toxic payloads attached tumor-associated antigen-targeting IgG antibody via an enzyme-cleavable linker that releases the drug inside cell. Aptamers are promising alternative antibodies in terms antigen targeting; however, their polynucleotide nature and smaller size result completely different PK/PD profile compared IgG. This may prove advantageous: owing lower molecular weight, aptamer-drug achieve better penetration solid tumors ADCs.

Language: Английский

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Branched Linkers for Homogeneous Antibody-Drug Conjugates: How Long Is Long Enough?

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(24), P. 13356 - 13356

Published: Dec. 12, 2024

Homogeneous antibody–drug conjugates (ADCs) exhibit significantly improved pharmacological properties compared to their heterogeneous counterparts. Site-specific conjugation of the payload IgG required for homogeneity can be achieved using enzymes. One example is microbial transglutaminase (MTGase), which selectively perform transamidation on Q295 residue human Fc when N297 glycans are removed. As a result, two modifications introduced per molecule; however, achieving higher drug-to-antibody ratios (DARs) requires use branched linkers. While several such linkers have been reported, little information available relationship between linker structure and ADC properties. To address this gap, we synthesized amino triazide linkers, differing by PEG4 fragment inserted after branching point, were used prepare homogeneous trastuzumab-based DAR 6 ADCs (a “short” “long” one). This was two-step process consisting enzymatic followed bioorthogonal coupling with cleavable bearing monomethyl auristatin E (MMAE). Two other trastuzumab–MMAE as controls: ADC, made conventional thiol–maleimide chemistry, 2 ADC. We found that, while four had identical affinity HER2, cytotoxicity differed significantly: just active its counterpart, but an order magnitude less potent, inferior even conjugate. Our findings indicate that length critically affects cytotoxic activity ADCs, possibly due steric hindrance influencing rate cleavage lysosomal

Language: Английский

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Unlocking the potential of melanotransferrin (CD228): implications for targeted drug development and novel therapeutic avenues

Expert Opinion on Therapeutic Targets, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 15, 2024

Introduction Melanotransferrin (CD228), a cell membrane-anchored protein, has emerged as significant cancer antigen due to its high expression in various solid tumors. This review synthesizes the current understanding and therapeutic potential of CD228.

Language: Английский

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