Cleavable Linkers to Enhance Selectivity of Antibody-Targeted Therapy of Cancer

Kukis, David L.; Novak‐Hofer, Ilse; DeNardo, Sally J.

doi:10.1089/10849780152752065

Cited by 16 publications

(50 citation statements)

References 25 publications

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“…62 Reduction of the kidney and liver radiation dose can be achieved through the use of cleavable linkers. 63 Pretargeted radionuclide delivery, however, seems the most promising strategy; dissociation of the targeting and toxicity delivery phases contributes to higher selective toxicity delivery at the target site while minimizing undesirable effects. Streptavidin (avidin)-biotin systems 64 or bispecific antibodies 65 have been adapted to pretargeting protocols.…”

Section: Radioimmunoconjugatesmentioning

confidence: 99%

Update: Recombinant Antibodies: From the Laboratory to the Clinic

Albrecht

DeNardo

2006

Cancer Biotherapy and Radiopharmaceuticals

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The development of recombinant antibodies has facilitated the exploitation of the Ab-Ag interaction specificity for targeted therapies. A fully human antibody, with custom integrated designs, can be obtained in one-third the time, compared to development of antibodies by hybridoma technology. Recombinant antibodies can be tailored for specific applications, "armed" with cytotoxic agents in a controllable fashion, and used for extracellular and intracellular targeting. Multitargeted and combination therapies are rapidly evolving for the treatment of cancer. Antibody therapeutics, costly to develop and produce, have proven beneficial in the clinic.

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Section: Radioimmunoconjugatesmentioning

confidence: 99%

Update: Recombinant Antibodies: From the Laboratory to the Clinic

Albrecht

DeNardo

2006

Cancer Biotherapy and Radiopharmaceuticals

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“…liver) without significantly affecting tumor retention thereby increasing the therapeutic index of the agent. [24] One of the research focuses of our laboratory has been the design of protease cleavable linkers for the development of diagnostic and radiotherapeutic drug delivery systems. The impetus for the development of linkers that are substrates for cathepsin B and S is the high level of expression of these proteases in MPS tissues.…”

Section: Introductionmentioning

confidence: 99%

177Lu-labeled HPMA copolymers utilizing cathepsin B and S cleavable linkers: Synthesis, characterization and preliminary in vivo investigation in a pancreatic cancer model

Ogbomo

Shi

Wagh

et al. 2013

Nuclear Medicine and Biology

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Introduction A major barrier to the advancement of therapeutic nanomedicines has been the non-target toxicity caused by the accumulation of the drug delivery systems in organs associated with the reticuloendothelial system, particularly the liver and spleen. Herein, we report the development of peptide based metabolically active linkers (MALs) that are enzymatically cleaved by cysteine cathepsin B and S, two proteases highly expressed in the liver and spleen. The overall goal of this approach is to utilize the MALs to lower the non-target retention and toxicity of radiolabeled drug delivery systems, thus resulting in higher diagnostic and radiotherapeutic efficacy. Methods In this study three MALs (MAL0, MAL1 and MAL2) were investigated. MAL1 and MAL2 are composed of known substrates of cathepsin B and S, respectively, while MAL0 is a non-cleavable control. Both MAL1 and MAL2 were shown to undergo enzymatic cleavage with the appropriate cathepsin protease. Subsequent to conjugation to the HPMA copolymer and radiolabeling with 177Lu, the peptide-polymer conjugates were renamed 177Lu- metabolically active copolymers (177Lu-MACs) with the corresponding designation 177Lu-MAC0, 177Lu-MAC1 and 177Lu-MAC2. Results In vivo evaluation of the 177Lu-MACs was performed in a HPAC human pancreatic cancer xenograft mouse model. 177Lu-MAC1 and 177Lu-MAC2 demonstrated 3.1 and 2.1 fold lower liver retention, respectively, compared to control (177Lu-MAC0) at 72 h post-injection. With regard to spleen retention, 177Lu-MAC1 and 177Lu-MAC2 each exhibited a nearly fourfold lower retention, relative to control, at the 72 h time point. However, the tumor accumulation of the 177Lu-MAC0 was two to three times greater than 177Lu-MAC1 and 177Lu-MAC2 at the same time point. The MAL approach demonstrated the capability of substantially reducing the non-target retention of the 177Lu-labeled HPMA copolymers. Conclusions While further studies are needed to optimize the pharmacokinetics of the 177Lu-MACs design, the ability of the MAL to significantly decrease non-target retention establishes the potential this avenue of research may have for the improvement of diagnostic and radiotherapeutic drug delivery systems.

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“…An additional crucial feature for the successful construction of an ADC is the conjugation chemistry of the linker–payload with the Ab . All these components (Ab, conjugation chemistry, linker, and payload) must be carefully optimized and clinically validated to obtain a potent and selective ADC that displays high chemical stability in circulation, preventing the premature drug release that very often leads to systemic toxicity . One of the crucial parameters in ADC architecture is the linker connecting the Ab with the drug.…”

Section: Antibody–drug Conjugatesmentioning

confidence: 99%

Protease‐activated prodrugs: strategies, challenges, and future directions

Poręba

2020

The FEBS Journal

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Proteases play critical roles in virtually all biological processes, including proliferation, cell death and survival, protein turnover, and migration. However, when dysregulated, these enzymes contribute to the progression of multiple diseases, with cancer, neurodegenerative disorders, inflammation, and blood disorders being the most prominent examples. For a long time, disease-associated proteases have been used for the activation of various prodrugs due to their well-characterized catalytic activity and ability to selectively cleave only those substrates that strictly correspond with their active site architecture. To date, versatile peptide sequences that are cleaved by proteases in a site-specific manner have been utilized as bioactive linkers for the targeted delivery of multiple types of cargo, including fluorescent dyes, photosensitizers, cytotoxic drugs, antibiotics, and pro-antibodies. This platform is highly adaptive, as multiple protease-labile conjugates have already been developed, some of which are currently in clinical use for cancer treatment. In this review, recent advancements in the development of novel protease-cleavable linkers for selective drug delivery are described. Moreover, the current limitations regarding the selectivity of linkers are Abbreviations AAC, antibody-antibiotic conjugate; Ab, antibody; ACC, 7-amino-4-carbamoylmethylcoumarin; ADAM, a disintegrin and metalloproteinase; ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; ADC, antibody-drug conjugate; aPSs, activatable photosensitizers; BHQ-3, black hole quencher 3; Boc, tert-butyloxycarbonyl group; BT20, a type of mammary gland carcinoma; Cas9, CRISPR-associated protein 9;

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Cleavable Linkers to Enhance Selectivity of Antibody-Targeted Therapy of Cancer

Cited by 16 publications

References 25 publications

Update: Recombinant Antibodies: From the Laboratory to the Clinic

Update: Recombinant Antibodies: From the Laboratory to the Clinic

177Lu-labeled HPMA copolymers utilizing cathepsin B and S cleavable linkers: Synthesis, characterization and preliminary in vivo investigation in a pancreatic cancer model

Protease‐activated prodrugs: strategies, challenges, and future directions

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