Modulation of drug-linker design to enhance in vivo potency of homogeneous antibody-drug conjugates

Pabst, Martin; McDowell, William; Manin, Anaïs; Kyle, Andrew F.; Camper, N. D.; Juan, Elena De; Parekh, Vimal; Rudge, Felicity; Makwana, Hiteshri; Kantner, Terrence; Parekh, Hemal; Michelet, Aurelie; Sheng, Xiao Bo; Popa, Gina; Tucker, Carolyn M.; Khayrzad, Farzad; Pollard, Derek; Kozakowska, Katarzyna; Resende, Ricardo; Jenkins, Alan; Simoes, Fabio; Morris, D. F. C.; Williams, Paul; Badescu, George; Baker, Matthew; Bird, Matthew; Frigerio, Mark; Godwin, Antony

doi:10.1016/j.jconrel.2017.02.027

Cited by 35 publications

(21 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…23 A later report published by Pabst and coworkers in 2017 demonstrated that the need for multiple high doses previously required for tumour growth inhibition was likely due to loss of the MMAE payload in circulation, prior to reaching the tumour. 24 This was revealed to be due to enzymatic cleavage of the valine-citrulline-PABC spacer by serum proteases and not due to chemical instability of the linker. 25 Through reagent optimization, it was observed that by shielding the valine-citrulline-PABC-MMAE moiety with a branched PEG 24 linker, more stable constructs can be produced.…”

Section: Bissulfonesmentioning

confidence: 99%

Homogeneous antibody-drug conjugates via site-selective disulfide bridging

Forte

Chudasama

Baker

2018

Drug Discovery Today: Technologies

View full text Add to dashboard Cite

Antibody-drug conjugates (ADCs) constructed using site-selective labelling methodologies are likely to dominate the next generation of these targeted therapeutics. To this end, disulfide bridging has emerged as a leading strategy as it allows the production of highly homogeneous ADCs without the need for antibody engineering. It consists of targeting reduced interchain disulfide bonds with reagents which reconnect the resultant pairs of cysteine residues, whilst simultaneously attaching drugs. The 3 main reagent classes which have been exemplified for the construction of ADCs by disulfide bridging will be discussed in this review; bissulfones, next generation maleimides and pyridazinediones, along with others in development.

show abstract

Section: Bissulfonesmentioning

confidence: 99%

Homogeneous antibody-drug conjugates via site-selective disulfide bridging

Forte

Chudasama

Baker

2018

Drug Discovery Today: Technologies

View full text Add to dashboard Cite

show abstract

“…(13,41), see Supplemental Material) indicating that the impact of tissue penetration is important across all ADCs studied to date. Since this publication(15) two other studies reported the same result –keeping the small molecule dose the same and increasing the antibody dose improved efficacy(37,42). However, a potentially confounding factor in these studies was that higher DAR ADCs tend to have faster clearance (DAR-dependent clearance), although the difference in payload AUC was less than 25%for these cases (42,43).…”

Section: Discussionmentioning

confidence: 66%

“…However, ADCs tend to have low IC50's, often over an order of magnitude below the K d (Fig. 2)(4,37,38), indicating sub-saturating concentrations can result in cell death. Therefore, the heterogeneous delivery of ADC in the tumor can result in “overkill” of perivascular cells, where they receive more therapeutic than what is needed, while other cells receive none.…”

Section: Discussionmentioning

confidence: 99%

Improved Tumor Penetration and Single-Cell Targeting of Antibody–Drug Conjugates Increases Anticancer Efficacy and Host Survival

et al. 2018

View full text Add to dashboard Cite

Current antibody-drug conjugates (ADC) have made advances in engineering the antibody, linker, conjugation site, small-molecule payload, and drug-to-antibody ratio (DAR). However, the relationship between heterogeneous intratumoral distribution and efficacy of ADCs is poorly understood. Here, we compared trastuzumab and ado-trastuzumab emtansine (T-DM1) to study the impact of ADC tumor distribution on efficacy. In a mouse xenograft model insensitive to trastuzumab, coadministration of trastuzumab with a fixed dose of T-DM1 at 3:1 and 8:1 ratios dramatically improved ADC tumor penetration and resulted in twice the improvement in median survival compared with T-DM1 alone. In this setting, the effective DAR was lowered, decreasing the amount of payload delivered to each targeted cell but increasing the number of cells that received payload. This result is counterintuitive because trastuzumab acts as an antagonist and has no single-agent efficacy, yet improves the effectiveness of T-DM1 Novel dual-channel fluorescence ratios quantified single-cell ADC uptake and metabolism and confirmed that the cellular dose of T-DM1 alone exceeded the minimum required for efficacy in this model. In addition, this technique characterized cellular pharmacokinetics with heterogeneous delivery after 1 day, degradation and payload release by 2 days, and cell killing and tumor shrinkage 2 to 3 days later. This work demonstrates that the intratumoral distribution of ADC, independent of payload dose or plasma clearance, plays a major role in ADC efficacy. This study shows how lowering the drug-to-antibody ratio during treatment can improve the intratumoral distribution of a antibody-drug conjugate, with implications for improving the efficacy of this class of cancer drugs. .

show abstract

“…It is the main reason for the failure of ADC in the clinical application that the concentration of payload is deficient to treat tumors on account of the DAR of ADC in clinical stage generally control to 3.5–4 (Beck et al, 2017). Thus, augmenting the hydrophilicity of ADC with high DAR by the design of drug-linker exquisitely will improve the efficacy in vivo (Pabst et al, 2017). Some hydrophilic groups such as PEG or PHF may improve this dilemma.…”

Section: The Payload-linker Linkagementioning

confidence: 99%

The Analysis of Key Factors Related to ADCs Structural Design

Tang

Liu

et al. 2019

Front. Pharmacol.

View full text Add to dashboard Cite

Antibody–drug conjugates (ADCs) have developed rapidly in recent decades. However, it is complicated to map out a perfect ADC that requires optimization of multiple parameters including antigens, antibodies, linkers, payloads, and the payload-linker linkage. The therapeutic targets of the ADCs are expected to express only on the surface of the corresponding target tumor cells. On the contrary, many antigens usually express on normal tissues to some extent, which could disturb the specificity of ADCs and limit their clinical application, not to mention the antibody is also difficult to choose. It requires to not only target and have affinity with the corresponding antigen, but it also needs to have a linkage site with the linker to load the payloads. In addition, the linker and payload are indispensable in the efficacy of ADCs. The linker is required to stabilize the ADC in the circulatory system and is brittle to release free payload while the antibody combines with antigen. Also, it is a premise that the dose of ADCs will not kill normal tissues and the released payloads are able to fulfill the killing potency in tumor cells at the same time. In this review, we mainly focus on the latest development of key factors affecting ADCs progress, including the selection of antibodies and antigens, the optimization of payload, the modification of linker, payload-linker linkage, and some other relevant parameters of ADCs.

show abstract

Modulation of drug-linker design to enhance in vivo potency of homogeneous antibody-drug conjugates

Cited by 35 publications

References 21 publications

Homogeneous antibody-drug conjugates via site-selective disulfide bridging

Homogeneous antibody-drug conjugates via site-selective disulfide bridging

Improved Tumor Penetration and Single-Cell Targeting of Antibody–Drug Conjugates Increases Anticancer Efficacy and Host Survival

The Analysis of Key Factors Related to ADCs Structural Design

Contact Info

Product

Resources

About