Promoting antigen escape from dendritic cell endosomes potentiates anti-tumoral immunity

Bikorimana, Jean-Pierre; Salame, Natasha; Beaudoin, Simon; Balood, Mohammad; Crosson, Théo; Abusarah, Jamilah; Talbot, Sébastien; Löbenberg, Raimar; Plouffe, Sebastien; Rafei, Moutih

doi:10.1016/j.xcrm.2022.100534

Cited by 8 publications

(42 citation statements)

References 36 publications

(78 reference statements)

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“…PKKKRKV represents the cNLS sequence taken from simian virus 40 (SV-40) large T antigen, while GYG and GG residues serve as N-and C-terminus spacers, respectively [12]. Conjugation of Accum to protein can be performed by using any conjugation technique, such as the cross-linker sulfosuccinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (sulfo-SMCC) reacting with the amine of lysine and the sulfhydryl moiety of cysteine via its NHS-ester and the maleimide reactive group of the cross-linker (Figure 1) [12,14,15]. ChAcNLS, or Accum, is water-soluble; has a positive net charge of +5 and a molecular weight of 1.8 kDa; and is synthetically recovered with ≥94% purity and a molecular mass of 1768.5 g/mol [12,14].…”

Section: Accum™: Genesis Of a Primermentioning

confidence: 99%

“…ChAcNLS, or Accum, is water-soluble; has a positive net charge of +5 and a molecular weight of 1.8 kDa; and is synthetically recovered with ≥94% purity and a molecular mass of 1768.5 g/mol [12,14]. Accum is added to conjugates in the same, or higher, molar excess ratio to yield Accum-modified conjugates [15]. During the modification process, free cross-linker and free Accum are eliminated by multiple centricon filtration and a Sephadex column, while Accum-modified conjugates are subsequently processed in ultrafiltration tubes, concentrated, and biochemically characterized with SDS-PAGE, turbidity assays, differential scanning fluorimetry, and protein concentration assays, followed by functional evaluation with conjugate-receptor affinity assays against naked or non-Accum-modified conjugates [14].…”

Section: Accum™: Genesis Of a Primermentioning

confidence: 99%

“…Molecules 2022, 27, 3807 2 of 13 Accum™ is a novel biotechnology exemplifying, in its initial concept, the need to circumvent the biological challenges of ADCs [10][11][12][13][14][15]. Despite their targeted therapy nature (a receptor-specific mAb linked to a cytotoxic payload), ADCs become captives of the cellular transport mechanisms they were designed to exploit to deposit their cargo in a trojan horse-like fashion [9].…”

Section: Introductionmentioning

confidence: 99%

“…Accum™ employs a ChAc-NLS fusion compound that enables its conjugate to override endosome entrapment and accumulate intracellularly in target cells [12,15]. The basis for exploiting ChAc, the bile acid moiety of Accum™, is that it allows nonenveloped viruses to escape endosomes [38] by inducing the metabolism of endosomal membrane sphingomyelin into ceramide, appending subsequent structural and dynamic membrane changes that promote endosome-to-cytoplasm protein traversal without killing cells [39][40][41][42].…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, the NLS moiety of Accum™ redirects trafficking of the conjugate to the nucleus; ultimately, both Accum moieties increase intracellular retention in target cells [12]. The concept of the ChAc-NLS fusion compound serving as a cell accumulator (Accum for short) has been shown to be pliable, with the potential for coupling to different molecular conjugates for use in different cancer settings [10][11][12][13][14][15]. In this review article, we discuss the genesis of Accum™ and highlight its docility in producing context-specific therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

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Accum™ Technology: A Novel Conjugable Primer for Onco-Immunotherapy

El-Kadiry

Beaudoin²,

Plouffe³

et al. 2022

Molecules

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Compromised activity is a common impediment for biologics requiring endosome trafficking into target cells. In cancer cells, antibody-drug conjugates (ADCs) are trapped in endosomes or subsequently pumped extracellularly, leading to a reduction in intracellular accumulation. In subsets of dendritic cells (DCs), endosome-engulfed antigens face non-specific proteolysis and collateral damage to epitope immunogenicity before proteasomal processing and subsequent surface presentation. To bypass these shortcomings, we devised Accum™, a conjugable biotechnology harboring cholic acid (ChAc) and a nuclear localization signal (NLS) sequence for endosome escape and prompt nuclear targeting. Combined, these mechanisms culminate in enhanced intracellular accumulation and functionalization of coupled biologics. As proof-of-principle, we have biochemically characterized Accum, demonstrating its adaptability to ADCs or antigens in different cancer settings. Additionally, we have validated that endosome escape and nuclear routing are indispensable for effective intracellular accumulation and guaranteed target cell selectivity. Importantly, we have demonstrated that the unique mechanism of action of Accum translates into enhanced tumor cytotoxicity when coupled to ADCs, and durable therapeutic and prophylactic anti-cancer immunogenicity when coupled to tumor antigens. As more pre-clinical evidence accumulates, the adaptability, unique mechanism of action, and high therapeutic potency of Accum signal a promising transition into clinical investigations in the context of onco-immunotherapy.

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Section: Accum™: Genesis Of a Primermentioning

confidence: 99%

Section: Accum™: Genesis Of a Primermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Accum™ Technology: A Novel Conjugable Primer for Onco-Immunotherapy

El-Kadiry

Beaudoin²,

Plouffe³

et al. 2022

Molecules

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Living Leukocyte‐Based Drug Delivery Systems

et al. 2023

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Leukocytes play a vital role in immune responses, including defending against invasive pathogens, reconstructing impaired tissue, and maintaining immune homeostasis. When the immune system is activated in vivo, leukocytes accomplish a series of orderly and complex regulatory processes. While cancer and inflammation‐related diseases like sepsis are critical medical difficulties plaguing humankind around the world, leukocytes have been shown to largely gather at the focal site, and significantly contribute to inflammation and cancer progression. Therefore, the living leukocyte‐based drug delivery systems have attracted considerable attention in recent years due to the innate and specific targeting effect, low immunogenicity, improved therapeutic efficacy, and low reverse effect. In this review, the recent advances in the development of living leukocyte‐based drug delivery systems including macrophages, neutrophils, and lymphocytes as promising treatment strategies for cancer and inflammation‐related diseases are introduced. The advantages, current challenges, and limitations of these delivery systems are also discussed, as well as perspectives on the future development of precision and targeted therapy in the clinics are provided. Collectively, it is expected that such kind of living cell‐based drug delivery system is promising to improve or even revolutionize the treatments of cancers and inflammation‐related diseases in the clinics.

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