A highly stable human single-domain antibody-drug conjugate exhibits superior penetration and treatment of solid tumors

Wu, Yanling; Li, Quanxiao; Yu, Ker‐Wei; Wang, Zhi; Cheng, Lei; Li, Ji; Ding, Lulu; Wang, Qianqian; Cheng, Yuanrong; Wei, Yaozhu; Song, Yuanlin; Yang, Zhenlin; Tu, Chao; Ding, Yu; Ying, Tianlei

doi:10.1016/j.ymthe.2022.04.013

Cited by 30 publications

(44 citation statements)

References 44 publications

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“…The next two steps, relating to the transport and local clearance of tumor-retained HCT-mono-mIL12 across the tumor interstitium (Figure 6, steps 2 and 3), are interpreted as a form of competition between tumor antigen binding and antigen-mediated local clearance (i.e., antigen metabolic turnover) versus the intratumoral diffusion mediated by Abantigen interactions. This is related to the concept of binding site barrier (7), as previously reported for tumor-targeted Abs (8,9) and Ab-drug conjugates (35)(36)(37). Thus, these steps are governed by the dissociation rate constant (k off ) of the Ab moiety for HER2 antigen: the slower the dissociation rate from the tumor surface antigen, the longer it takes to transport over a given distance (6).…”

Section: Discussionmentioning

confidence: 63%

Improved intratumoral penetration of IL12 immunocytokine enhances the antitumor efficacy

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 63%

Improved intratumoral penetration of IL12 immunocytokine enhances the antitumor efficacy

et al. 2022

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“…The intrinsic stability of sdAbs as exemplified by the inherent thermostability and chemostability, enables sdAbs to withstand prolonged storage [ 36 , 68 , 105 , 106 ]. For instance, sdAbs are with tolerance towards pH ranging from 3 to 11, also with resistance to chemical denaturant (0.35 - 8 M urea) [ [107] , [108] , [109] , 105 , 110 ]. Therefore, sdAbs can be reserved as a stockpile of therapeutic options for future epidemic.…”

Section: Single-domain Antibody As An Attractive Neutralizing Solutio...mentioning

confidence: 99%

Single domain antibodies derived from ancient animals as broadly neutralizing agents for SARS-CoV-2 and other coronaviruses

Lim

Kok

Lim

et al. 2022

Biomedical Engineering Advances

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“…The increase of this enzyme yield is particularly observed in certain types of cancer, including NHL. Additionally, a recent study reported its use in the construction of a sdAb-based ADC which suggests it possesses adequate physicochemical properties (hydrophobicity and potency) to build our new sdAb-drug conjugate 52 . Moreover, SN-38 has already proven clinical efficacy, being used as payload in a recently FDA-approved ADC, Sacituzumab govitecan (Trodelvy), indicated for the treatment of metastatic triple negative breast cancer 53 .…”

Section: Discussionmentioning

confidence: 99%

Rabbit derived VL single-domains as promising scaffolds to generate antibody–drug conjugates

André

Dias

Aguiar

et al. 2023

Sci Rep

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Antibody–drug conjugates (ADCs) are among the fastest-growing classes of therapeutics in oncology. Although ADCs are in the spotlight, they still present significant engineering challenges. Therefore, there is an urgent need to develop more stable and effective ADCs. Most rabbit light chains have an extra disulfide bridge, that links the variable and constant domains, between Cys80 and Cys171, which is not found in the human or mouse. Thus, to develop a new generation of ADCs, we explored the potential of rabbit-derived VL-single-domain antibody scaffolds (sdAbs) to selectively conjugate a payload to Cys80. Hence, a rabbit sdAb library directed towards canine non-Hodgkin lymphoma (cNHL) was subjected to in vitro and in vivo phage display. This allowed the identification of several highly specific VL-sdAbs, including C5, which specifically target cNHL cells in vitro and present promising in vivo tumor uptake. C5 was selected for SN-38 site-selective payload conjugation through its exposed free Cys80 to generate a stable and homogenous C5-DAB-SN-38. C5-DAB-SN-38 exhibited potent cytotoxicity activity against cNHL cells while inhibiting DNA-TopoI activity. Overall, our strategy validates a platform to develop a novel class of ADCs that combines the benefits of rabbit VL-sdAb scaffolds and the canine lymphoma model as a powerful framework for clinically translation of novel therapeutics for cancer.

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A highly stable human single-domain antibody-drug conjugate exhibits superior penetration and treatment of solid tumors

Cited by 30 publications

References 44 publications

Improved intratumoral penetration of IL12 immunocytokine enhances the antitumor efficacy

Improved intratumoral penetration of IL12 immunocytokine enhances the antitumor efficacy

Single domain antibodies derived from ancient animals as broadly neutralizing agents for SARS-CoV-2 and other coronaviruses

Rabbit derived VL single-domains as promising scaffolds to generate antibody–drug conjugates

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