A homogeneous high-DAR antibody–drug conjugate platform combining THIOMAB antibodies and XTEN polypeptides

Zacharias, Neelie; Park, Summer; Zheng, Bing; Loyet, Kelly M.; Xu, Min; Kozak, Katherine R.; Phillips, Gail Lewis; Shen, Ben-Quan; Wu, Cong; Morisaki, J. Hiroshi; Xu, Keyang; Kamath, Amrita V.; Rowntree, Rebecca K.; Reilly, Dorothea; Pillow, Thomas H.; Polson, Andrew G.; Schellenberger, Volker; Hazenbos, Wouter L. W.; Sadowsky, Jack; Yu, Shang‐Fan; Chuh, Josefa; Barry, Hilda Hernandez-; Yip, Victor; Podust, Vladimir N.; Kajihara, Kimberly K.; Leipold, Douglas D.; Li, Guangmin; Dong, Eugene; Paluch, Maciej; Fischer, David; Zheng, Kai; Lei, Corinna; Rosario, Geoffrey Del; Ng, Carl; Su, Dian; Liu, Luna; Masih, Shabkhaiz; He, Jintang; Sawyer, William S.; Tinianow, Jeff N.; Mařı́k, Jan

doi:10.1039/d1sc05243h

Cited by 30 publications

(18 citation statements)

References 41 publications

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“…Then we focused on determining the DAR values for the developed ANC. Increasing the DAR for ADCs to be more than 4:1 has been a longstanding challenge, which has significantly impeded the further development of ADCs. − Our ANC platform uniquely positioned us to address this challenge by increasing the DAR without compromising the stability and targeting capability of antibodies. We performed theoretical calculations of DAR values based on reasonable assumptions in the physical properties such as density and volume of our nanogel.…”

Section: Resultsmentioning

confidence: 99%

Targeted Drug Delivery Using a Plug-to-Direct Antibody–Nanogel Conjugate

Huynh

Qiu

et al. 2023

Biomacromolecules

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Targeted drug delivery using antibody–drug conjugates has attracted great attention due to its enhanced therapeutic efficacy compared to traditional chemotherapy. However, the development has been limited due to a low drug-to-antibody ratio and laborious linker-payload optimization. Herein, we present a simple and efficient strategy to combine the favorable features of polymeric nanocarriers with antibodies to generate an antibody–nanogel conjugate (ANC) platform for targeted delivery of cytotoxic agents. Our nanogels stably encapsulate several chemotherapeutic agents with a wide range of mechanisms of action and solubility. We showcase the targetability of ANCs and their selective killing of cancer cells over-expressing disease-relevant antigens such as human epidermal growth factor receptor 2, epidermal growth factor receptor, and tumor-specific mucin 1, which cover a broad range of breast cancer cell types while maintaining low to no toxicity to non-targeted cells. Overall, our system represents a versatile approach that could impact next-generation nanomedicine in antibody-targeted therapeutics.

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Section: Resultsmentioning

confidence: 99%

Targeted Drug Delivery Using a Plug-to-Direct Antibody–Nanogel Conjugate

Huynh

Qiu

et al. 2023

Biomacromolecules

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“…From a different perspective, antibodies and ADC can also help to eliminate bacterial pathogens through opsonization, that is, binding to bacterium, possibly attracting complement proteins, and in doing so facilitating phagocytosis by neutrophils. 18,19 This mode of action relies on the recognition between the Fc part of the antibody/ADC by the neutrophils and/or by the complement proteins, and this cognate interaction can possibly be altered by design of ADC. To investigate this, we used the Newman Δspa/Δsbi_mAm strain of S. aureus which expresses the fluorescent protein mAmetrine.…”

Section: Adcs Associate With the Surface Of S Aureus And Retain Immun...mentioning

confidence: 99%

“…Arguably the most prominent example of an ADC for the treatment of bacterial diseases (also termed antibodyantibiotic conjugates, AAC) is the one whereby the antibody binds a bacterium and through opsonization facilitates the uptake of the pathogen by the immune cells. 18,19 Here, a rifamycin analogue was conjugated to this antibody using a cathepsin-sensitive linker such that drug release was mediated by mammalian proteases, within the immune cells. 18,19 Apart from this successful case, examples of ADCs developed for the treatment of bacteria are few.…”

Section: Introductionmentioning

confidence: 99%

“…18,19 Here, a rifamycin analogue was conjugated to this antibody using a cathepsin-sensitive linker such that drug release was mediated by mammalian proteases, within the immune cells. 18,19 Apart from this successful case, examples of ADCs developed for the treatment of bacteria are few. 20 In large part, this is because bacteria do not perform receptor-mediated endocytosis.…”

Section: Introductionmentioning

confidence: 99%

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Antibody-drug conjugates to treat bacterial biofilms

Tvilum

Johansen

Glud

et al. 2023

Preprint

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Implant-associated infections remain a grand unmet medical need because they involve biofilms that protect bacteria from the immune system and harbour antibiotic-tolerant persister cells. There is an urgent need for new biofilm-targeting therapies with antimicrobials, to treat these infections via a non-surgical way. In this work, we address this urgent medical need and engineer antibody-drug conjugates (ADC) that kill bacteria in suspension and in biofilms, in vitro and in vivo. The ADC contains an anti-neoplastic drug mitomycin C, which is also a potent antimicrobial against biofilms. While most ADCs are clinically validated as anti-cancer therapeutics where the drug is released after internalisation of the ADC in the target cell, the ADCs designed herein release the conjugated drug without cell entry. This is achieved with a novel mechanism of drug, which likely involves an interaction of ADC with thiols on the bacterial cell surface. ADC targeted towards bacteria were superior by the afforded antimicrobial effects compared to the non-specific counterpart, in suspension and within biofilms, in vitro and in vivo. An implant-associated murine osteomyelitis model was then used to demonstrate the ability of the antibody to reach the infection, and the superior antimicrobial efficacy compared to standard antibiotic treatment in vivo. Our results illustrate the development of ADCs into a new area of application with a significant translational potential.

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“…ADCs have achieved great successes in clinical and several drugs have been approved by FDA 6 . However, one major challenge is the limitation of drug to antibody ratio (DAR) 7,8 due to the limited number of thiol-or amine-groups available on the antibody surface 9 . Increasing copies of drugs can also lead to heterogeneity or aggregation, which are problems for reagent preparation and e cacy evaluation 10 .…”

Section: Introductionmentioning

confidence: 99%

Phase separation enhanced drug delivery system for anti-cancer therapy

Bai

Pei

Duan

et al. 2022

Preprint

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The cellular phase-separated condensates compartmentalize and concentrate biomolecules with distinct physicochemical properties, which has great potential for therapy purposes. However, the discovered phase separation phenomena in living organisms were restricted intracellularly, which limits the biomedical application of phase separation. Here, we designed a phase separation enhanced delivery system to specifically condensate molecules on the cell surface for efficient drug delivery. As a proof of concept, we demonstrated that an anti-cancer drug conjugate can selectively co-phase separate with the targeting component on cancer cell surface and efficiently kill the cells after internalization. Both cellular and in vivo assays showed more potency with this system than traditional antibody conjugates. The method provides insights in the application of phase separation as a powerful tool for therapeutic purpose.

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A homogeneous high-DAR antibody–drug conjugate platform combining THIOMAB antibodies and XTEN polypeptides

Abstract: The antibody-drug conjugate (ADC) is a well-validated modality for the cell-specific delivery of small molecules with impact expanding rapidly beyond their originally-intended purpose of treating cancer. However, antibody-mediated delivery (AMD)...

Cited by 30 publications

References 41 publications

Targeted Drug Delivery Using a Plug-to-Direct Antibody–Nanogel Conjugate

Targeted Drug Delivery Using a Plug-to-Direct Antibody–Nanogel Conjugate

Antibody-drug conjugates to treat bacterial biofilms

Phase separation enhanced drug delivery system for anti-cancer therapy

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