Abstract:Targeted delivery of chemotherapeutics aims to increase efficacy and lower toxicity by concentrating drugs at the site-of-action, a method embodied by the seven current FDA-approved antibody–drug conjugates (ADC). However, a variety of pharmacokinetic challenges result in relatively narrow therapeutic windows for these agents, hampering the development of new drugs. Here, we use a series of prostate-specific membrane antigen–binding single-domain (Humabody) ADC constructs to demonstrate that tissue penetration… Show more
“…S1). This is similar to the result seen in a prostate cancer model with an ADC targeting PSMA (29). Together with the different sensitivities between clinical patient tumors, this is likely a major confounding factor for why a clear correlation between target expression and efficacy has not been found.…”
Section: Aacrjournalsorgsupporting
confidence: 78%
“…1) and previous examples (27,31). Improved tissue penetration of a single-domain anti-PSMA antibody also showed improved efficacy over larger constructs (29) when using the DGN549 payload. A computational analysis by Khera and colleagues (11) indicates that these results are due to the higher efficiency of direct cell killing relative to bystander killing.…”
Several antibody-drug conjugates (ADC) showing strong clinical responses in solid tumors target high expression antigens (HER2, TROP2, Nectin-4, and folate receptor alpha/FRa). Highly expressed tumor antigens often have significant low-level expression in normal tissues, resulting in the potential for target-mediated drug disposition (TMDD) and increased clearance. However, ADCs often do not cross-react with normal tissue in animal models used to test efficacy (typically mice), and the impact of ADC binding to normal tissue antigens on tumor response remains unclear. An antibody that cross-reacts with human and murine FRa was generated and tested in an animal model where the antibody/ADC bind both human tumor FRa and mouse FRa in normal tissue. Previous work has demonstrated that a "carrier" dose of unconjugated antibody can improve the tumor penetration of ADCs with high expression target-antigens. A carrier dose was employed to study the impact on cross-reactive ADC clearance, distribution, and efficacy. Co-administration of unconjugated anti-FRa antibody with the ADC-improved efficacy, even in low expression models where co-administration normally lowers efficacy. By reducing target-antigen-mediated clearance in normal tissue, the coadministered antibody increased systemic exposure, improved tumor tissue penetration, reduced target-antigen-mediated uptake in normal tissue, and increased ADC efficacy. However, payload potency and tumor antigen saturation are also critical to efficacy, as shown with reduced efficacy using too high of a carrier dose. The judicious use of higher antibody doses, either through lower DAR or carrier doses, can improve the therapeutic window by increasing efficacy while lowering target-mediated toxicity in normal tissue.
“…S1). This is similar to the result seen in a prostate cancer model with an ADC targeting PSMA (29). Together with the different sensitivities between clinical patient tumors, this is likely a major confounding factor for why a clear correlation between target expression and efficacy has not been found.…”
Section: Aacrjournalsorgsupporting
confidence: 78%
“…1) and previous examples (27,31). Improved tissue penetration of a single-domain anti-PSMA antibody also showed improved efficacy over larger constructs (29) when using the DGN549 payload. A computational analysis by Khera and colleagues (11) indicates that these results are due to the higher efficiency of direct cell killing relative to bystander killing.…”
Several antibody-drug conjugates (ADC) showing strong clinical responses in solid tumors target high expression antigens (HER2, TROP2, Nectin-4, and folate receptor alpha/FRa). Highly expressed tumor antigens often have significant low-level expression in normal tissues, resulting in the potential for target-mediated drug disposition (TMDD) and increased clearance. However, ADCs often do not cross-react with normal tissue in animal models used to test efficacy (typically mice), and the impact of ADC binding to normal tissue antigens on tumor response remains unclear. An antibody that cross-reacts with human and murine FRa was generated and tested in an animal model where the antibody/ADC bind both human tumor FRa and mouse FRa in normal tissue. Previous work has demonstrated that a "carrier" dose of unconjugated antibody can improve the tumor penetration of ADCs with high expression target-antigens. A carrier dose was employed to study the impact on cross-reactive ADC clearance, distribution, and efficacy. Co-administration of unconjugated anti-FRa antibody with the ADC-improved efficacy, even in low expression models where co-administration normally lowers efficacy. By reducing target-antigen-mediated clearance in normal tissue, the coadministered antibody increased systemic exposure, improved tumor tissue penetration, reduced target-antigen-mediated uptake in normal tissue, and increased ADC efficacy. However, payload potency and tumor antigen saturation are also critical to efficacy, as shown with reduced efficacy using too high of a carrier dose. The judicious use of higher antibody doses, either through lower DAR or carrier doses, can improve the therapeutic window by increasing efficacy while lowering target-mediated toxicity in normal tissue.
“…Proper dosing of antibody-based biologics is an important factor in improving tissue penetration and thus therapeutic efficacy for treating solid tumors 5,6 . Antibody-drug conjugates (ADCs), which combine the antigen specificity of antibody and the potency of cytotoxic agents, are an emerging class of antibody bioconjugates that could benefit from improved tissue penetration 7,8 . Owing to the dose-limiting toxicities of the potent cytotoxic payload, ADCs are usually administered at a much lower dose with narrower therapeutic window compared to their parent antibodies, which may result in decreased penetration into solid tumors.…”
Poor tissue penetration remains a major challenge for antibody-based therapeutics of solid tumors, but proper dosing can improve the tissue penetration and thus therapeutic efficacy of these biologics. Due to dose-limiting toxicity of the small molecule payload, antibody-drug conjugates (ADCs) are administered at a much lower dose than their parent antibodies, which further reduces tissue penetration. We conducted an early-phase clinical trial (NCT02415881) and previously reported the safety of an antibody-dye conjugate (panitumumab-IRDye800CW) as primary outcome. Here, we report a retrospective exploratory analysis of the trial to evaluate whether co-administration of an unconjugated antibody could improve the intratumoral distribution of the antibody-dye conjugate in patients. By measuring the multiscale distribution of the antibody-dye conjugate, this study demonstrates improved microscopic antibody distribution without increasing uptake (toxicity) in healthy tissue when co-administered with the parent antibody, supporting further clinical investigation of the co-administration dosing strategy to improve the tumor penetration of ADCs.
“…In multiple mouse xenograft models, ABD-DOX resulted in greater tumor regression than Aldoxorubicin, DOX-prodrug under clinical development that was designed to covalently bind endogenous serum albumin. Other notable examples of albumin-based delivery systems involve the genetic fusion of ABD to various therapeutic proteins including affibodies [ 165 , 166 ], human soluble complement receptor type 1 [ 167 ], single chain antibody-drug conjugates [ 168 ], insulin-like growth factor II [ 169 ], immunotoxins [ 170 ], and respiratory syncytial virus subgroup A (RSV-A) G protein (G2Na) [ 171 ]. Fig.…”
Engineering protein and peptide-based materials for drug delivery applications has gained momentum due to their biochemical and biophysical properties over synthetic materials, including biocompatibility, ease of synthesis and purification, tunability, scalability, and lack of toxicity. These biomolecules have been used to develop a host of drug delivery platforms, such as peptide- and protein-drug conjugates, injectable particles, and drug depots to deliver small molecule drugs, therapeutic proteins, and nucleic acids. In this review, we discuss progress in engineering the architecture and biological functions of peptide-based biomaterials —naturally derived, chemically synthesized and recombinant— with a focus on the molecular features that modulate their structure-function relationships for drug delivery.
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