Minimising the payload solvent exposed hydrophobic surface area optimises the antibody-drug conjugate properties

RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 15(3), P. 832 - 838

Published: Jan. 1, 2024

Minimising solvent exposed hydrophobic surface area of payload is identified as a critical design parameter for optimising ADC drug-like properties.

Language: Английский

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The medicinal chemistry evolution of antibody–drug conjugates

RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 15(3), P. 809 - 831

Published: Jan. 1, 2024

Antibody-drug conjugates (ADCs) comprise 3 components of wildly differing sizes: antibody (150 000 Da), linker (typically <500 Da) and payload Da). While the drug-linker makes up only a small percent ADC it has disproportionately massive impact on all aspects ADC. Replacing maleimide with bromoacetamide (BrAc) affords stable attachment to cysteine, supports total flexibility for design more homogenous Optimisation protease cleavable dipeptide reduces aggregation, facilitates moderation physicochemical properties enables long-term stability facilitate subcutaneous self-administration. Payloads are designed specifically afford optimal Structural information SAR guide improve both potency selectivity molecule target improving therapeutic index resulting ADCs. Minimising solvent exposed hydrophobic surface area improves drug-like ADC, realisation that heteroatom can be than just site as also drive adoption prodrug strategy at project initiation key areas medicinal chemistry drives. For an symbiotic relationship three structurally disparate requires they function in unison huge role ensure this happens.

Language: Английский

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Fundamental properties and principal areas of focus in antibody-drug conjugates formulation development

Antibody Therapeutics, Journal Year: 2025, Volume and Issue: unknown

Published: March 9, 2025

Abstract Antibody–drug conjugates (ADCs) have emerged as a rapidly expanding class of therapeutics driven by their superior specificity and clinical efficacy. 14 out 16 commercially approved ADCs are formulated lyophilized forms because ADC is generally considered to be less stable than unmodified antibody. The formulation development for ADCs, particularly liquid formulation, presents unique challenges due intricate structural complexity, physicochemical properties, degradation pathways. This review provides the first comprehensive analysis strategies employed in commercial ADCs. Furthermore, this discusses key areas focus throughout workflow, spanning from initial final stage drug product manufacturing. In addition, we identify analyze distinctive technical compared unconjugated antibody, while proposing potential solutions these challenges. Finally, offer strategic perspectives on future directions advance promising therapeutic modality.

Language: Английский

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Advances And Challenges in Immunosuppressive Antibody Drug Conjugates

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 117576 - 117576

Published: March 1, 2025

Language: Английский

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Bispecific Antibodies Produced via Chemical Site-Specific Conjugation Technology: AJICAP Second-Generation

ACS Medicinal Chemistry Letters, Journal Year: 2023, Volume and Issue: 14(12), P. 1767 - 1773

Published: Nov. 21, 2023

Bispecific antibodies (BisAbs) are biotherapeutics that amalgamate the specificities of two distinct into one molecule, however, their engineering requires genetic modification and remains time-consuming. Therefore, we used AJICAP second-generation technology, which drives production site-specific conjugation without requirements, to generate BisAbs. Using haloketone chemistry as an alternative maleimide chemistry, successfully produced antibody conjugates. Pharmacokinetic studies revealed haloketone-based conjugate was stable in rat plasma. The resultant BisAbs were rigorously evaluated, surface plasmon resonance measurements flow cytometry analyses confirmed antigen binding remained intact. Additionally, affinity for neonatal Fc receptor (FcRn) retained after conjugation. Further cytotoxicity evaluation emphasized pronounced activity generated This novel approach introduces a fully chemical, strategy capable producing BisAbs, heralding new era field biotherapeutics.

Language: Английский

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Anti-TNF Thioester Glucocorticoid Antibody–Drug Conjugate Fully Inhibits Inflammation with Minimal Effect on Systemic Corticosterone Levels in a Mouse Arthritis Model

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(11), P. 9495 - 9515

Published: May 23, 2024

We describe the discovery of a thioester-containing glucocorticoid receptor modulator (GRM) payload and corresponding antibody-drug conjugate (ADC). Payload

Language: Английский

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Discovery and Evaluation of TLR-Targeted Immune Agonists

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(18), P. 16222 - 16234

Published: Sept. 5, 2024

Toll-like receptor (TLR) activation converts immunologically inactive tumors into active by activating tumor residing antigen-presenting cells and recruitment of cytotoxic T lymphocytes. Targeted immune agonists (TIAs) are antibody drug conjugates with small-molecule TLR agonist payloads. The mechanism action TIAs involves antigen recognition, Fcγ-receptor-dependent phagocytosis, TLR-mediated to drive killing myeloid cells. Several new low DAR anti-HER2 conjugated novel TLR7 or dual-TLR7/8 cleavable noncleavable linkers were synthesized profiled. In vitro studies demonstrated that these activate only in the presence antigen-expressing cancer Evaluation ELISpot-based assays confirmed immunogenicity constructs. Systemic administration tumor-bearing mice resulted reduction at doses. These results provide a strong rationale for further development as class immunotherapeutics.

Language: Английский

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Antibody drug conjugates beyond cytotoxic payloads

Progress in medicinal chemistry, Journal Year: 2023, Volume and Issue: unknown, P. 1 - 59

Published: Jan. 1, 2023

Language: Английский

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Impact of dipeptide on ADC physicochemical properties and efficacy identifies Ala–Ala as the optimal dipeptide

RSC Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 15(1), P. 355 - 365

Published: Nov. 27, 2023

A glucocorticoid receptor modulator (GRM) was conjugated to a mouse anti-TNF antibody using various dipeptide linkers. Impact of linkers on ADC physical properties, including solubility, hydrophobicity, and aggregation were evaluated.

Language: Английский

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Linker substitution influences succinimide ring hydrolysis equilibrium impacting the stability of attachment to antibody–drug conjugates

RSC Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 15(2), P. 612 - 622

Published: Nov. 27, 2023

Maleimide is used in antibody–drug conjugate (ADC) generation to attach the drug-linker antibody. linkers with hydrolysis-enabled maleimides were designed. Corresponding ADCs made and subjected thermal stress, succinimide ring hydrolysis drug release measured.

Language: Английский

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