Removal of interstitial hyaluronan with recombinant human hyaluronidase improves the systemic and lymphatic uptake of cetuximab in rats

Styles, Ian K.; Feeney, Orlagh M.; Nguyen, Tri‐Hung; Brundel, Daniel H.S.; Kang, Dong Hyun; Clift, Renee; McIntosh, Michelle Paula; Porter, Christopher John

doi:10.1016/j.jconrel.2019.10.040

Cited by 17 publications

(6 citation statements)

References 43 publications

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“…Clinical studies confirmed the potential of this approach to improve the pharmacokinetic profiles of co-administered mAb (e.g. rituximab, trastuzumab, cetuximab) compared to subcutaneous injection without rHuPH20 ( Printz et al, 2020 ; Shpilberg & Jackisch, 2013 ; Styles et al, 2019 ). Another study achieved a comparable body exposure to trastuzumab after subcutaneous injection at 8 mg/kg as compared to intravenous injection at 6 mg/kg ( Wynne et al, 2013 ).…”

Section: Extracellular Barriersmentioning

confidence: 83%

Therapeutic antibodies – natural and pathological barriers and strategies to overcome them

Ojaimi

Blin

Lamamy

et al. 2022

Pharmacology & Therapeutics

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Antibody-based therapeutics have become a major class of therapeutics with over 120 recombinant antibodies approved or under review in the EU or US. This therapeutic class has experienced a remarkable expansion with an expected acceleration in 2021–2022 due to the extraordinary global response to SARS-CoV2 pandemic and the public disclosure of over a hundred anti-SARS-CoV2 antibodies. Mainly delivered intravenously, alternative delivery routes have emerged to improve antibody therapeutic index and patient comfort. A major hurdle for antibody delivery and efficacy as well as the development of alternative administration routes, is to understand the different natural and pathological barriers that antibodies face as soon as they enter the body up to the moment they bind to their target antigen. In this review, we discuss the well-known and more under-investigated extracellular and cellular barriers faced by antibodies. We also discuss some of the strategies developed in the recent years to overcome these barriers and increase antibody delivery to its site of action. A better understanding of the biological barriers that antibodies have to face will allow the optimization of antibody delivery near its target. This opens the way to the development of improved therapy with less systemic side effects and increased patients’ adherence to the treatment.

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Section: Extracellular Barriersmentioning

confidence: 83%

Therapeutic antibodies – natural and pathological barriers and strategies to overcome them

Ojaimi

Blin

Lamamy

et al. 2022

Pharmacology & Therapeutics

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“…To circumvent this serious issue, one strategy consists in combining Abs with hyaluronidase. Hyaluronidase degrades hyaluronic acid, lowering the amount of negatively charged molecules and enhancing the bioavailability of Ab after SC injection [ 33 ]. Moreover, combining Abs with hyaluronidase may facilitate bulk fluid flow and improve the pharmacokinetic profile after SC injection [ 34 ], as demonstrated in multiple clinical studies [ 35 , 36 , 37 ].…”

Section: Routes Of Administration For Therapeutic Antibodiesmentioning

confidence: 99%

Alternative Routes of Administration for Therapeutic Antibodies—State of the Art

2022

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Background: For the past two decades, there has been a huge expansion in the development of therapeutic antibodies, with 6 to 10 novel entities approved each year. Around 70% of these Abs are delivered through IV injection, a mode of administration allowing rapid and systemic delivery of the drug. However, according to the evidence presented in the literature, beyond the reduction of invasiveness, a better efficacy can be achieved with local delivery. Consequently, efforts have been made toward the development of innovative methods of administration, and in the formulation and engineering of novel Abs to improve their therapeutic index. Objective: This review presents an overview of the routes of administration used to deliver Abs, different from the IV route, whether approved or in the clinical evaluation stage. We provide a description of the physical and biological fundamentals for each route of administration, highlighting their relevance with examples of clinically-relevant Abs, and discussing their strengths and limitations. Methods: We reviewed and analyzed the current literature, published as of the 1 April 2022 using MEDLINE and EMBASE databases, as well as the FDA and EMA websites. Ongoing trials were identified using clinicaltrials.gov. Publications and data were identified using a list of general keywords. Conclusions: Apart from the most commonly used IV route, topical delivery of Abs has shown clinical successes, improving drug bioavailability and efficacy while reducing side-effects. However, additional research is necessary to understand the consequences of biological barriers associated with local delivery for Ab partitioning, in order to optimize delivery methods and devices, and to adapt Ab formulation to local delivery. Novel modes of administration for Abs might in fine allow a better support to patients, especially in the context of chronic diseases, as well as a reduction of the treatment cost.

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“…Deliberate alterations in fluid homeostasis through the use of albumin [101] or odematogenic agents [102,103] can increase convective flow to the lymphatics. Alternatively, local removal of bulky interstitial components such as the glycosaminoglycan hyaluronan can improve lymphatic access and facilitate the administration of high volume doses of therapeutics in the skin [104].…”

Section: Parenteral Drug Delivery; Targeting Immunotherapeutics To Th...mentioning

confidence: 99%

“…In contrast, the interstitial transfer of cationic macromolecules can be impeded by interactions with the negatively charged interstitium [105]. Increases in osmotic pressure and deliberate removal of interstitial components such as hyaluronan may also facilitate interstitial flow and promote lymphatic transport of macromolecules [104].…”

Section: Parenteral Drug Delivery; Targeting Immunotherapeutics To Th...mentioning

confidence: 99%

“…IV (rather than SC) administration of immunotherapies can result in lymphatic transport from the interstitial space after extravasation from capillary beds [90,91,104,105,114]. This strategy however, relies on long circulating properties in order to achieve sufficient concentrations in the interstitium to drive lymphatic drainage.…”

Section: Using IV Administration To Access Lymphatics More Generallymentioning

confidence: 99%

See 1 more Smart Citation

Lymph-directed immunotherapy – Harnessing endogenous lymphatic distribution pathways for enhanced therapeutic outcomes in cancer

Feeney

Gracia

Brundel

et al. 2020

Advanced Drug Delivery Reviews

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Removal of interstitial hyaluronan with recombinant human hyaluronidase improves the systemic and lymphatic uptake of cetuximab in rats

Cited by 17 publications

References 43 publications

Therapeutic antibodies – natural and pathological barriers and strategies to overcome them

Therapeutic antibodies – natural and pathological barriers and strategies to overcome them

Alternative Routes of Administration for Therapeutic Antibodies—State of the Art

Lymph-directed immunotherapy – Harnessing endogenous lymphatic distribution pathways for enhanced therapeutic outcomes in cancer

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