Subcutaneous Administration of a Zwitterionic Chitosan‐Based Hydrogel for Controlled Spatiotemporal Release of Monoclonal Antibodies
Thomas Gréa
(1, 2)
,
Guillaume Jacquot
(3, 4, 5)
,
Arthur Durand
(1, 6)
,
Clélia Mathieu
(3, 5)
,
Adeline Gasser
(3, 5)
,
Chen Zhu
(3, 5, 7)
,
Mainak Banerjee
(3, 5, 7)
,
Elyse Hucteau
(3, 8)
,
Joris Mallard
(3, 8, 9)
,
Pedro Lopez Navarro
(3, 5)
,
Bogdan Popescu
(3, 5)
,
Eloise Thomas
(10)
,
David Kryza
(10)
,
Jacqueline Sidi-Boumedine
(10)
,
Giuseppe Ferrauto
(11)
,
Eliana Gianolio
(11)
,
Guillaume Fleith
(12)
,
Jérôme Combet
(12)
,
Susana Brun
(13)
,
Stéphane Erb
(5, 14, 7)
,
Sarah Cianferani
(5, 14, 7)
,
Loïc Charbonnière
(7)
,
Lyne Fellmann
(15)
,
Céline Mirjolet
(16, 17)
,
Laurent David
(2)
,
Olivier Tillement
(1)
,
François Lux
(1, 18)
,
Sébastien Harlepp
(3, 5)
,
Xavier Pivot
(3, 5)
,
Alexandre Detappe
(3, 5, 7)
1
iLM - FENNEC -
iLM - Formation, élaboration de nanomatériaux et cristaux
2 IMP - Ingénierie des Matériaux Polymères
3 ICANS - Institut de Cancérologie de Strasbourg Europe
4 Nano-H SAS [Saint-Quentin Fallavier]
5 IMS [Strasbourg] - Institut du Médicament de Strasbourg
6 MexBrain
7 IPHC - Institut Pluridisciplinaire Hubert Curien
8 CRBS - Centre de Recherche en Biomédecine de Strasbourg
9 MSP - Mitochondrie, Stress oxydant et Protection musculaire
10 LAGEPP - Laboratoire d'automatique, de génie des procédés et de génie pharmaceutique
11 UNITO - Università degli studi di Torino = University of Turin
12 ICS - Institut Charles Sadron
13 POLY-DTECH
14 LSMBO - Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg]
15 SILABE - Simian Laboratory Europe
16 UNICANCER/CRLCC-CGFL - Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon]
17 TIRECS - Thérapies et réponse immunitaire dans les cancers (CTM UMR 1231)
18 IUF - Institut universitaire de France
2 IMP - Ingénierie des Matériaux Polymères
3 ICANS - Institut de Cancérologie de Strasbourg Europe
4 Nano-H SAS [Saint-Quentin Fallavier]
5 IMS [Strasbourg] - Institut du Médicament de Strasbourg
6 MexBrain
7 IPHC - Institut Pluridisciplinaire Hubert Curien
8 CRBS - Centre de Recherche en Biomédecine de Strasbourg
9 MSP - Mitochondrie, Stress oxydant et Protection musculaire
10 LAGEPP - Laboratoire d'automatique, de génie des procédés et de génie pharmaceutique
11 UNITO - Università degli studi di Torino = University of Turin
12 ICS - Institut Charles Sadron
13 POLY-DTECH
14 LSMBO - Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg]
15 SILABE - Simian Laboratory Europe
16 UNICANCER/CRLCC-CGFL - Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon]
17 TIRECS - Thérapies et réponse immunitaire dans les cancers (CTM UMR 1231)
18 IUF - Institut universitaire de France
David Kryza
- Fonction : Auteur
- PersonId : 174200
- IdHAL : david-kryza
- ORCID : 0000-0002-3765-2964
- IdRef : 092739717
Loïc Charbonnière
- Fonction : Auteur
- PersonId : 754902
- IdHAL : loic-charbonniere
- ORCID : 0000-0003-0328-9842
- IdRef : 103911596
Laurent David
- Fonction : Auteur
- PersonId : 178602
- IdHAL : laurentdavid
- ORCID : 0000-0003-3632-8537
- IdRef : 063767627
Sébastien Harlepp
- Fonction : Auteur
- PersonId : 755072
- ORCID : 0000-0001-8891-7953
- IdRef : 083502866
Xavier Pivot
- Fonction : Auteur
- PersonId : 1361199
- ORCID : 0000-0003-3689-5013
Alexandre Detappe
- Fonction : Auteur
- PersonId : 772112
- ORCID : 0000-0001-9364-1621
Résumé
Abstract Subcutaneous (SC) administration of monoclonal antibodies (mAbs) is a proven strategy for improving therapeutic outcomes and patient compliance. The current FDA‐/EMA‐approved enzymatic approach, utilizing recombinant human hyaluronidase (rHuPH20) to enhance mAbs SC delivery, involves degrading the extracellular matrix's hyaluronate to increase tissue permeability. However, this method lacks tunable release properties, requiring individual optimization for each mAb. Seeking alternatives, physical polysaccharide hydrogels emerge as promising candidates due to their tunable physicochemical and biodegradability features. Unfortunately, none have demonstrated simultaneous biocompatibility, biodegradability, and controlled release properties for large proteins (≥150 kDa) after SC delivery in clinical settings. Here, a novel two‐component hydrogel comprising chitosan and chitosan@DOTAGA is introduced that can be seamlessly mixed with sterile mAbs formulations initially designed for intravenous (IV) administration, repurposing them as novel tunable SC formulations. Validated in mice and nonhuman primates (NHPs) with various mAbs, including trastuzumab and rituximab, the hydrogel exhibited biodegradability and biocompatibility features. Pharmacokinetic studies in both species demonstrated tunable controlled release, surpassing the capabilities of rHuPH20, with comparable parameters to the rHuPH20+mAbs formulation. These findings signify the potential for rapid translation to human applications, opening avenues for the clinical development of this novel SC biosimilar formulation.