Dissecting the impact of target-binding kinetics of protein binders on tumor localization

Song, Yunjin; Jeong, Hyo Jin; Kim, Song‐Rae; Ryu, Yiseul; Baek, Jonghwi; Kwon, Jinhak; Cho, Hyeongjun; Kim, Kil-Nam; Lee, Joong-Jae

doi:10.1016/j.isci.2021.102104

Cited by 3 publications

(1 citation statement)

References 48 publications

(83 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An exceedingly high-affinity Ab tends to penetrate only a few cell layers outside the blood vessels due to tight antigen binding and/ or depletion by antigen-mediated internalization and lysosomal degradation before its dissociation from the antigen on cells, thereby limiting the intratumoral diffusion (6,7). This concept is known as the binding-site barrier (7), which explains the poor tumor tissue penetration and spread of a high-affinity Ab compared with those of lower-affinity Ab in solid tumors (8)(9)(10). Likewise, tumor-targeted Ab-based immunocytokines would face the same challenges for solid tumors.…”

Section: Introductionmentioning

confidence: 99%

Improved intratumoral penetration of IL12 immunocytokine enhances the antitumor efficacy

et al. 2022

View full text Add to dashboard Cite

Tumor-targeting antibody (Ab)-fused cytokines, referred to as immunocytokines, are designed to increase antitumor efficacy and reduce toxicity through the tumor-directed delivery of cytokines. However, the poor localization and intratumoral penetration of immunocytokines, especially in solid tumors, pose a challenge to effectively stimulate antitumor immune cells to kill tumor cells within the tumor microenvironment. Here, we investigated the influence of the tumor antigen-binding kinetics of a murine interleukin 12 (mIL12)-based immunocytokine on tumor localization and diffusive intratumoral penetration, and hence the consequent antitumor activity, by activating effector T cells in immunocompetent mice bearing syngeneic colon tumors. Based on tumor-associated antigen HER2-specific Ab Herceptin (HCT)-fused mIL12 carrying one molecule of mIL12 (HCT-mono-mIL12 immunocytokine), we generated a panel of HCT-mono-mIL12 variants with different affinities (KD) mainly varying in their dissociation rates (koff) for HER2. Systemic administration of HCT-mono-mIL12 required an anti-HER2 affinity above a threshold (KD = 130 nM) for selective localization and antitumor activity to HER2-expressing tumors versus HER2-negative tumors. However, the high affinity (KD = 0.54 or 46 nM) due to the slow koff from HER2 antigen limited the depth of intratumoral penetration of HCT-mono-mIL12 and the consequent tumor infiltration of T cells, resulting in inferior antitumor activity compared with that of HCT-mono-mIL12 with moderate affinity of (KD = 130 nM) and a faster koff. The extent of intratumoral penetration of HCT-mono-mIL12 variants was strongly correlated with their tumor infiltration and intratumoral activation of CD4+ and CD8+ T cells to kill tumor cells. Collectively, our results demonstrate that when developing antitumor immunocytokines, tumor antigen-binding kinetics and affinity of the Ab moiety should be optimized to achieve maximal antitumor efficacy.

show abstract

Section: Introductionmentioning

confidence: 99%

Improved intratumoral penetration of IL12 immunocytokine enhances the antitumor efficacy

et al. 2022

View full text Add to dashboard Cite

show abstract

Turn On, Tune In, Turnover! Target Biology Impacts In Vivo Potency, Efficacy, and Clearance

Gabrielsson¹,

Stephan

2023

Pharmacol Rev

View full text Add to dashboard Cite

Unraveling the Mechanism of Epichaperome Modulation by Zelavespib: Biochemical Insights on Target Occupancy and Extended Residence Time at the Site of Action

Sharma,

Joshi,

Kalidindi

et al. 2023

Biomedicines

View full text Add to dashboard Cite

Drugs with a long residence time at their target sites are often more efficacious in disease treatment. The mechanism, however, behind prolonged retention at the site of action is often difficult to understand for non-covalent agents. In this context, we focus on epichaperome agents, such as zelavespib and icapamespib, which maintain target binding for days despite rapid plasma clearance, minimal retention in non-diseased tissues, and rapid metabolism. They have shown significant therapeutic value in cancer and neurodegenerative diseases by disassembling epichaperomes, which are assemblies of tightly bound chaperones and other factors that serve as scaffolding platforms to pathologically rewire protein–protein interactions. To investigate their impact on epichaperomes in vivo, we conducted pharmacokinetic and target occupancy measurements for zelavespib and monitored epichaperome assemblies biochemically in a mouse model. Our findings provide evidence of the intricate mechanism through which zelavespib modulates epichaperomes in vivo. Initially, zelavespib becomes trapped when epichaperomes bound, a mechanism that results in epichaperome disassembly, with no change in the expression level of epichaperome constituents. We propose that the initial trapping stage of epichaperomes is a main contributing factor to the extended on-target residence time observed for this agent in clinical settings. Zelavespib’s residence time in tumors seems to be dictated by target disassembly kinetics rather than by frank drug–target unbinding kinetics. The off-rate of zelavespib from epichaperomes is, therefore, much slower than anticipated from the recorded tumor pharmacokinetic profile or as determined in vitro using diluted systems. This research sheds light on the underlying processes that make epichaperome agents effective in the treatment of certain diseases.

show abstract

Dissecting the impact of target-binding kinetics of protein binders on tumor localization

Cited by 3 publications

References 48 publications

Improved intratumoral penetration of IL12 immunocytokine enhances the antitumor efficacy

Improved intratumoral penetration of IL12 immunocytokine enhances the antitumor efficacy

Turn On, Tune In, Turnover! Target Biology Impacts In Vivo Potency, Efficacy, and Clearance

Unraveling the Mechanism of Epichaperome Modulation by Zelavespib: Biochemical Insights on Target Occupancy and Extended Residence Time at the Site of Action

Contact Info

Product

Resources

About