The Subcutaneous Route of Administration for Therapeutic Antibodies: Comparison
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Therapeutic antibodies (Abs) are used in the treatment of numerous diseases, including infection, cancer, and autoimmune disorders, in which they have already demonstrated their efficacy. The success of Abs is due to (I) a high level of specificity and affinity to their target antigen, (II) a favorable safety profile, and (III) a unique pharmacokinetic profile, supporting a longer half-life as compared to other drugs. While the majority of Abs are delivered through IV injection, evidence in the literature showed that beyond the reduction of invasiveness, a better efficacy could be achieved with a local delivery of Abs. Among those routes, one has been in full development these last few years, with already good clinical results and still promising developments : The Subcutaneous route.

  • Subcutaneous delivery
  • Drug Administration
  • Therapeutic Antibodies
  • Clinical Trials

1. Introduction

Over the past 30 years, therapeutic antibodies (Abs) have been found to be valuable therapeutics [1]. A total of 6 to 12 new Abs are approved by the U.S. FDA and/or the EMA each year, and new molecules are reaching clinical trials every month [2]. Therapeutic antibodies are used in the treatment of numerous diseases, including infection, cancer, and autoimmune disorders, in which they have already demonstrated their efficacy [3][4].
The success of Abs is due to (I) a high level of specificity and affinity to their target antigen, (II) a favorable safety profile, and (III) a unique pharmacokinetic profile, supporting a longer half-life as compared to other drugs [5]. These characteristics have allowed Abs to move rapidly from pre-clinical studies to clinical trials, as observed during the COVID-19 pandemic [6].
From the historical full-length antibody, molecular engineering has enabled the development of multiple and diverse Ab formats, including multi-specific Abs, fragments, and conjugated Abs that are now extensively evaluated in clinical trials [7].
Due to their intrinsic biological properties, Abs have a specific interconnected pharmacokinetic and pharmacodynamic profile, which influence their absorption and biodistribution after administration [5]. Abs pharmacokinetics is linked to their route of administration [8]. Historically, Abs were delivered via intravenous (IV) injection. Nowadays, the subcutaneous (SC) route is often used for chronic diseases [9]. These systemic routes have the advantage of allowing the delivery of large amounts of Abs and to enable rapid systemic bioavailability. However, one of their drawbacks is the limited distribution from the site of injection via the blood flow to the diseased organ, which may result in limited Ab amount in the vicinity of the target antigen. Ultimately, this necessitates the injection of a high dose, which may be associated with potential toxicity and cost issues. Accumulating preclinical evidence has driven researchers to reconsider Abs’ route of administration in order to maximize their therapeutic index.
Alternative delivery methods, addressing Abs to the disease site (e.g., delivery of Abs in the lung to treat respiratory pathologies [10], or inside a tumor [11]) have emerged and progressed to the clinical trial stage. In theory, a higher concentration of the antibody at the target site should improve the therapeutic response, while lowering the concentration in neighboring healthy tissues, resulting in reduced side effects. One of those favorable route of administration, discussed here, is the subcutaneous injection.

2. The Subcutaneous Route: The Most Popular after IV Injection

2.1. Fundamentals Related to the SC Route

After IV injection, the second most popular route for the delivery of antibodies is the subcutaneous (SC) route. It consists in the injection of Abs using a syringe and needle under the skin of patients at an angle of 90 °C, thus bypassing the barrier formed by the epidermis and dermis layers [12]. The choice of the anatomical site is important due to differences in dermal thickness which may reduce the absorption of the injected Abs. Nowadays, around 30% of the approved Abs are delivered by SC injection (Table 1). If the delivery of drugs, mainly opioids, by SC administration, has been in practice since the middle of the 19th century, the administration of Abs by this route is recent. The first subcutaneous injected Ab was Adalimumab, used in the treatment of rheumatoid arthritis and approved by the FDA in 2002, and by the EMA in 2003 [13]. After this first success, and particularly since 2009, the number of marketed Abs delivered by the SC route has significantly increased. It is noteworthy that SC administration is already the standard route in the treatment of chronic diseases such as rheumatoid arthritis. Indeed, it allows self-administration and improves patients’ compliance. The SC route is mainly used for the delivery of Abs targeting interleukins such as TNF-α, critically involved in the development of rheumatoid arthritis (Adalimumab, Golimumab, Certolizumab pegol) or cytokine receptors such as the IL-17a receptor, involved in the progression of psoriasis (Brodalumab, Secukinumab, Ixekizumab) [14]. The development of Abs intended for a subcutaneous injection necessitates understanding the physiology of the skin. After injection, the drug reaches the hypodermis interstitial space between the dermis and the deep fascia covering the muscle tissue. This layer is composed of adipose tissue, blood, lymph vessels, and resident immune cells such as fibroblasts and macrophages. All components are enmeshed in an extracellular matrix (ECM) network, rich in collagen, elastin, and glycosaminoglycans [15]. To pass into the systemic compartment (via either the blood capillaries or lymphatic vessels), and thus reach their target, Abs have to diffuse through the ECM, which constitutes both a physical and chemical barrier. The fate of the Ab is dictated by its size, charge, and affinity with transporters. Despite the presence of the positively charged collagen fibrils, the hypodermis interstitial space displayed an overall negative charge due to important concentrations of hyaluronic acid and chondroitin sulfate, two major glycosaminoglycans of the hypodermis ECM, which are negatively charged. The global negative charge of ECM favors the transport of negatively charged drugs thanks to electrostatic repulsion [16]. However, the majority of therapeutic Abs are positively charged. Once the ECM is traversed, drugs may enter the systemic circulation by two different mechanisms. Molecules smaller than 16 kDa diffuse directly into the bloodstream, taking advantage of the permeability of the vascular endothelium [16]. However, Abs, along with drugs with a higher molecular weight, are absorbed by convection into lymphatic vessels. Thus, the subcutaneous route is particularly interesting to target lymphoid cells and the molecules they secrete. Abs in the lymphatic vessels pass to larger lymphatics and then reach the blood vascular system, from where they diffuse throughout the body. If the development of Abs for subcutaneous injection is quite challenging, multiple factors explain the attractiveness of this route as compared to other parenteral ones. In the hypodermis, the walls in the fat lobule are thinner than those in the dermis, which facilitates the diffusion of drugs into blood capillaries [17]. Moreover, the absence of antigen-presenting cells in the hypodermis, usually present in the top layers of the skin (Langerhans cells and/or macrophages), may decrease the immunogenicity of the antibody. Thus, an increasing number of Abs delivered by SC are being developed, allowing a quicker delivery time of administration as compared to IV injection, enabling longer dosing intervals and, in fine, reducing the frequency of administration. In addition, SC administration is less invasive and painful than IV injection [16] and allows self-delivery at home [18]. Thus, the subcutaneous route may improve patient comfort and compliance, which is critical for the treatment of chronic diseases, and may be associated with a reduction in treatment costs, consuming fewer healthcare resources.

2.2. Abs Approved for Subcutaneous Delivery

Abs approved for subcutaneous administration must be formulated at a high concentration, thus necessitating a careful control of their stability and formulation viscosity. Different strategies have been considered to ensure the efficient absorption and bioavailability of Abs after hypodermis injection. They include, but are not limited to, the increase in delivered Abs concentration (e.g., SC administration limiting the injection volume to 1–2 mL [19]), the development of specific formulations to reduce physical and chemical destabilization (e.g., the use of polysorbate preventing aggregation and particle formation [20]) and the development of novel administration devices (e.g., the autoinjectors enabling a faster delivery for larger concentrations of Abs [21]). Those strategies have led to the approval of around 40 different Abs (Table 1).
Table 1.
Therapeutic antibodies approved by the Food and Drug Administration (FDA) or the European Medicine Agency (EMA) for subcutaneous administration.
International Non-Proprietary Name Trade Name Target Indication Format Sponsoring Company Year of Approval (FDA) Year of Approval (EMA)
ClinicalTrials.gov—Identifiers
Adalimumab Humira TNF-α Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis, Crohn disease Human full-length IgG1 AbbVie Inc. 2002 2003
Efalizumab
Casirivimab + Imdevimab Spike protein SARS-CoV2 Human full-length IgG1 cocktail Regeneron Pharmaceuticals URR (EMA + FDA) NCT05074433
Raptiva CD11a Psoriasis Humanized full-length IgG1 Merck Biopharma/Serono Europe 2003 1
Ofatumumab 12004 1
CD20 Relapsing multiple sclerosis Human full-length IgG1 Novartis Pharmaceuticals Phase 3 (Recruiting) NCT04486716

NCT04510220

NCT04353492		 Omalizumab Xolair IgE Severe Asthma
CSL312 (Garadacimab) Factor XIIaHumanized full-length IgG1 Genentech/Novartis 2003 2005
Hereditary Angioedema Human full-length IgG4 CSL Behring Phase 3 (Active, not recruiting) NCT04656418 Certolizumab Pegol Cimzia TNF-α Crohn Disease Humanized PEGylated Fab’ IgG1 fragment UCB Pharma 2008 2009
SAR440340 /REGN3500 (Itepekimab) IL-33 COPD Human full-length IgG4 Sanofi Phase 3 (Recruiting) NCT04701983 NCT04751487 Canakinumab Ilaris IL-1β Cryopirin-Associated Periodic Syndromes Human full-length IgG1 Novartis 2009 2009
JS002 (Ongericimab) PCSK9 Heterozygous Familial Hypercholesterolemia; Hyperlipidemia Human full-length IgG4 Shanghai Junshi Bioscience Co., Ltd. Phase 3 (Recruiting) NCT05325203 NCT04781114 Golimumab Simponi TNF-α Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis Human full-length IgG1 Centocor Ortho Biotech/Janssen Biologics 2009 2009
BCD-085 (Netakimab) IL-17 Psioratic Arthritis Humanized genetically modified IgG1 Biocad Phase 3 (Active, not recruiting) NCT03598751 Ustekinumab Stelara IL-12 and IL-23 Psoriasis Human full-length IgG1 Centocor Ortho Biotech/Janssen Cilag International
AK002 (Lirentelimab) Siglec-82009 2009
Eosinophilic Gastritis and/or Eosinophilic Duodenitis Humanized non fucosylated IgG1 Allakos, Inc. Phase 3 (Recruiting) NCT05152563 Denosumab Prolia RANK-L
MW032 RANK-L Bone Metastases from solid tumorsPostmenopausal Osteoporosis Human full-length IgG2 Amgen 2010 Human full-length IgG22010
Abwell (Shanghai) Bioscience Co., Ltd. Phase 3 (Active, not recruiting) NCT04812509 Tocilizumab Actemra/RoActemra IL-6R Rheumatoid Arthritis, Polyarticular Juvenile Idiopathic Arthritis, Systemic Juvenile Idiopathic Arthritis Humanized full-length IgG1 Genentech/Roche 2013 2014
Tralokinumab 1 IL-13 Atopic Dermatitis Human full-length IgG4 LEO Pharma Phase 3 (Recruiting) NCT05194540 NCT03587805 Alirocumab Praluent PCSK9
Golimumab LDL-C Lowering 1 TNF-aHuman full-length IgG1 Sanofi-Aventis 2015 2015
Moderately to Severely Active Ulcerative Colitis Human full-length IgG1 Janssen Research & Development, LLC Phase 3 (Recruiting) NCT03596645 Evolocumab Repatha PCSK9 LDL-C Lowering Human full-length IgG2 Amgen 2015 2015
Mepolizumab Nucala IL-5 Severe Asthma Humanized full-length IgG1 GlaxoSmithKline 2015 2015
Secukinumab Cosentyx IL-17a Psoriasis Human full-length IgG1 Novartis 2015
LY01011 RANK-L Bone Metastases from solid tumors Human full-length IgG2 Luye Pharma Group Ltd. Phase 3 (Recruiting) NCT04859569
QL1206 RANK-L Bone Metastases from solid tumors Human full-length IgG2 Qilu Pharmaceutical Co., Ltd. Phase 3 (Recruiting) NCT04550949 2015
Adalimumab 1 TNF-a Ulcerative Colitis Human full-length IgG1 AbbVie Phase 3 (Active, not recruiting) NCT02632175 Daclizumab Zinbryta IL-2 receptor-α Multiple Sclerosis Humanized full-length IgG1 Biogen 2016 2 2016 2
IBI306 PCSK9 Homozygous and Heterozygous Familial Hypercholesterolemia Human full-length IgG2 Innovent Biologics (Suzhou) Co., Ltd. Phase 3 (Recruiting) NCT04031742

NCT04709536

NCT04179669		 Ixekizumab Taltz IL-17a Psoriasis Humanized full-length IgG4 Eli Lilly 2016 2016
Alirocumab 1 PCSK9 Postprandial Hyperlipemia in Type 2 Diabetes Human full-length IgG1 Regeneron Pharmaceuticals Phase 3 (Recruiting) NCT03344692 Dupilumab Dupixent IL4 receptor-α Atopic Dermatitis Human full-length IgG4 Regeneron Pharmaceuticals/Sanofi-Aventis 2017 2017
SYN023 (CTB-011 and CTB-012) Sarilumab Kevzara IL-6 receptor Rheumatoid Arthritis Human full-length IgG1 Regeneron Pharmaceuticals/Sanofi-Aventis 2017 2017
Guselkumab Tremfya IL-23 p19 Psoriasis Human full-length IgG1 Janssen Biotech/Johnson & Johnson 2017 2017
Brodalumab Siliq/Kyntheum IL-17 receptor-α Psoriasis Human full-length IgG2 Valeant Pharmaceuticals/Leo Pharma 2017 2017
Benralizumab Fasenra IL-5 receptor-α Severe Asthma Humanized full-length IgG1 AstraZeneca 2017 2018
Emicizumab Hemlibra Factor IX and X Hemophilia A Humanized full-length bispecific IgG4 Genentech/Roche 2017 2018
Proteins of human Rabies Human Rabies Humanized full-length IgG cocktail Synermore Biologics (Suzhou) Co., Ltd. Phase 3 (Active, not recruiting) NCT04644484
Adalimumab 1 TNF-a Uveitis Human full-length IgG1 JHSPH Center for Clinical Trials Phase 3 (Recruiting) NCT03828019 Phase 3 (Recruiting) NCT05251909
Elranatamab + Daratumumab BCMA-CD3 + CD38 Multiple Myeloma Humanized) bispecific IgG2 + Human full-length IgG1 Pfizer Phase 3 (Recruiting) NCT05020236
Teclistamab BCMA-CD3+ Hematological Malignancies Human bispecific IgG4 Janssen Research & Development, LLC Phase 3 (Recruiting) NCT03145181 Rituximab and hyaluronidase Rituxan Hycela/MabThera SC
PRO 140 (Leronlimab) CCR5CD20 Follicular Lymphoma, Diffuse large B cell Lymphoma, and Chronic Lymphocytic Leukemia Chimeric full-length IgG1 HIV Humanized full-length IgG4 CytoDyn, Inc.Genentech/Roche 2017 2014
Phase 3 (Active, not recruiting) NCT03902522

NCT05271370

NCT02859961

NCT02990858		 Belimumab Benlysta BAFF Systemic Lupus Erythematosus Human full-length IgG1 GlaxoSmithKline 2017 2017
Tildrakizumab Ilumya/Ilumetri IL-23 p19 Psoriasis Humanized full-length IgG1 Merck Sharp & Dohme Corp/Almirall 2018
CM310 IL-4Ra Atopic Dermatitis2018
Humanized full-length IgG Keymed Biosciences Co., Ltd. Phase 3 (Not yet Recruiting) NCT05265923
Olokizumab IL-6 COVID-19 Humanized full-length IgG4 Burosumab
Benralizumab  R-Pharm Phase 3 (Recruiting) NCT05187793
Etrolizumab α4-β7/αE-β7 integrin receptor Crohn’s disease Humanized full-length IgG1 Hoffmann-La Roche Phase 3 (Recruiting) NCT02403323 Crysvita FGF23 X-linked Hypophosphatemia Human full-length IgG1 Ultragenyx Pharmaceutical/Kyowa Kirin Holdings 2018 2018
1
Gantenerumab β-amyloid Alzheimer’s disease Human full-length IgG1 Hoffmann-La Roche Phase 3 (Recruiting) Erenumab Aimovig CGRP Migraine Human full-length IgG2 Amgen/Novartis 2018 2018
IL-5Ra NCT03444870

NCT05256134

NCT04374253 Lanadelumab Takhzyro pKal Hereditary Angioedema Human full-length IgG1 2018 2018
Eosinophilic Gastritis and/or Gastroenteritis

Galcanezumab Emgality CGRP Migraine Humanized full-length IgG4 Eli Lilly 2019 2018
Humanized full-length IgG1 AstraZeneca NCT01760005
Emicizumab 1 FIX, FX Hemophilia A Without Inhibitor Humanized bispecific IgG4 Margaret Ragni, University of Pittsburgh Phase 3 (Recruiting) Takeda Pharmaceuticals Caplacizumab 3 Cablivi A1 from factor Willebrand Acquired Thrombocytopenic Thrombotic Purpura Humanized bivalent nanobody Sanofi-Aventis 2019 2018
Romosozumab Evenity RANK-L Postmenopausal Osteoporosis Humanized full-length IgG2 Amgen/UCB Pharma 2019 2019
Trastuzumab and hyaluronidase Herceptin Hylecta HER2 HER2+ Breast Cancer Humanized full-length IgG1 Genentech, inc./Roche 2019 2013
Risankizumab Skyrizi IL-23 p19 Psoriasis Humanized full-length IgG1 AbbVie Inc. 2019 2019
NCT04303559 Fremanezumab Ajovy CGRP Migraine Humanized full-length IgG2 Teva Branded Pharmaceutical Products R&D 2020 2019
Daratumumab and hyaluronidase Darzalex Faspro CD38 Light-chain Amyloidosis, Multiple Myeloma Human full-length IgG1 Janssen Biotech 2020 2020
Satralizumab Enspryng IL-6 receptor Neuromyelitis Optical Spectrum Disorder Humanized full-length IgG2 Genentech/Roche 2020 2021
Ofatumumab Kesimpta CD20 Multiple Sclerosis Human full-length IgG1 Novartis Pharmaceuticals Corporation 2020 2021
Pertuzumab, Trastuzumab, and hyaluronidase Phesgo HER2 Early Breast Cancer Humanized full-length IgG1 Genentech/Roche 2020 2020
Tralokinumab Adtralza IL-13 Eczema Human full-length IgG4 Leo Pharma A/S 2021 -
Tezepelumab Tezspire TSLP Asthma Human full-length IgG2 AstraZeneca 2021 -
1 The approval for Efalizumab was revoked, due to important side effects, by both the FDA and the EMA in 2009. 2 The approval for Daclizumab was revoked, due to important side effects, by both the FDA and the EMA in 2018. 3 The first dose of Caplacizumab is delivered through IV while the subsequent ones are delivered through SC. Data were obtained from the list of approved medicines and drugs by both agencies, and from the prescribing information provided by the manufacturers [22][23]. Abbreviations: TNF-α—Tumor Necrosis Factor alpha; IL—Interleukin; CD—Cluster of Differentiation; RANK-L—Receptor Activator of Nuclear factor Kappa-B ligand; PCSK9—Proprotein Convertase Subtilisin Kexin Type 9; BAFF—B-cell activating factor; FGF23—Fibroblast Growth Factor 23; Ig—Immunoglobulin; CGRP—Calcitonin gene-related peptide; PKal—Plasma Kallikrein; HER2—Human Epidermal Growth factor receptor 2; TSLP—Thymic Stromal Lymphopoietin.
A major concern for SC injection is the isoelectric point (pI) of Abs, found between 7 and 9, making Abs positively charged at the physiological pH. A study by Bumbaca Yadav et al., showed that positively charged Abs present a reduced bioavailability by 31%, while their negatively charged counterparts demonstrate enhanced bioavailability up to 70% after SC administration [24]. Another study found that the reduced bioavailability of Abs delivered subcutaneously is due to their interaction with ECM components, thus limiting the amount of Ab reaching the vascular compartment [25]. Moreover, the overall negative charge of the hypodermis interstitial space increases the interaction of ECM components with water molecules resulting in a low hydraulic conductivity and limiting the subcutaneous injection volume [26]. 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 [27]. Moreover, combining Abs with hyaluronidase may facilitate bulk fluid flow and improve the pharmacokinetic profile after SC injection [28], as demonstrated in multiple clinical studies [29][30][31]. Based on these results, the regulatory agencies approved Rituximab, Trastuzumab, and Daratumumab in combination with recombinant human hyaluronidase (rHuPH20), in 2017 (Rituxan Hycela/mAbThera s.c), 2019 (Herceptin Hylecta), and 2020 (Darzalex Faspro), respectively. These encouraging results have fueled the repurposing of Abs approved for delivery by IV injection to this novel modality of administration. Notably, Tocilizumab ((Ro)-Actemra), an antibody used in the treatment of rheumatoid polyarthritis, was formulated for the SC route, in response to patient demand, and to allow a less invasive route for a treatment usually delivered monthly [32]. It is noteworthy that multiple studies have demonstrated the absence of significant differences between the IV and SC routes of administration for Abs, thus making SC a legitimate option for patients [31][32].

2.3. Abs in Clinical Development for the SC Route

The clinical development of subcutaneously-delivered Ab concerns either de novo development, expansion of the disease target, and/or new formulation for already approved Abs. A high number of those Abs are currently found in clinical trials. Here, wresearchers listed subcutaneously delivered Abs either in active phase 3 trials or under review by regulatory agencies (Table 2).
Table 2. Therapeutic antibodies delivered by SC administration, currently undergoing review (URR) by the FDA and/or the EMA, and in active phase 3 of clinical development.
International Non- Proprietary Name or Code Name Target Indication Format Primary Sponsor Clinical Study Phase
1 Those antibodies are already on the market, either delivered by another route, or for another application. Data were obtained from clinicaltrials.gov and EMA/FDA’s website. Abbreviations: IL—Interleukin; CD—Cluster of Differentiation; COPD—Chronic obstructive pulmonary disease; PSCK—Proprotein convertase subtilisin/kexin; RANK-L—receptor activator of nuclear factor kappa-B ligand; TNF—Tumor Necrosis factor; BCMA—B-cell maturation antigen; TSLP—Thymic stromal lymphopoietin; HNGF—Human nerve growth factor; CCR—C-C chemokine receptor; FIX—Factor IX; FX—Factor X.
Novel developments include Fasinumab, a recombinant fully human IgG4, targeting the nerve growth factor (NGF) and evaluated for pain relief in patients suffering from osteoarthritis (OA). A phase 2b/3 trial showed that Fasinumab provides improvement in OA pain and motor function, even in patients that are non-responsive to analgesics [33]. The drug approval is pending an evaluation by the FDA (NCT03161093; NCT02683239). In the meantime, studies are also investigating lower doses of Fasinumab in patients with knee or hip OA. The repurposing of IV delivery approved Abs for SC application in a disease context different than the original approval is also investigated. For example, Ofatumumab (Arzerra®, Novartis) is a monoclonal antibody targeting CD20 and causing cytotoxicity in cells expressing CD20. It was first approved in 2010 for the treatment of certain chronic lymphocytic leukaemia by IV injection, and has been reformulated (Kesimpta) for SC administration and evaluated in patients with relapsed multiple sclerosis. Two ongoing phase 3 trials, OLIKOS (NCT04486716) and ARTIOS (NCT04353492) are evaluating the efficacy, safety, and tolerability of the SC drug in patients with relapsing multiple sclerosis, all of whom are transitioning from a CD20 Ab therapy (Rituximab or Ocrelizumab), or dimethyl fumarate therapy [34]. Many Abs have been developed or repurposed as emergency treatments since the beginning of the SARS-CoV2 pandemic, and target either the virus or the host inflammatory response. Among them, REGEN-COV2 comprising Casirivimab and Imdevimab has been approved for emergency use by IV infusion and is now undergoing regulatory review, for its use by SC administration to treat and prevent SARS-CoV-2 infection in non-hospitalized individuals [35]. The first phases of its clinical investigation showed a significant efficacy with improved survival. A phase 3 trial is also in progress to evaluate its potency for the prevention of COVID-19 in immunocompromised patients (NCT05074433).

2.4. Conclusion and Perspectives Regarding the Subcutaneous Route

The relevance of the SC route for the administration of Abs has been illustrated by several clinical successes. However, the bioavailability of Abs delivered subcutaneously remains difficult to predict. Advances in preclinical models would be necessary to investigate the fate of Abs at the SC injection site and their diffusion into the blood/lymphatic compartment. Interestingly, novel in vitro tools have been developed to predict the in vivo absorption of biopharmaceuticals after SC injection, by modeling the environmental changes an Ab will experience after its injection. Among those, Scissor (Subcutaneous Injection Site Simulator) device provides a tractable method to study the fate and the pharmacokinetics of biopharmaceuticals once in the hypodermis [36][37]. Nevertheless, as no in vitro model is yet accurate enough, the pharmacokinetics of Abs still relies on in vivo studies. Formulating Abs for the SC route remains challenging, as formulations need to afford high concentration with low viscosity, aggregation and immunogenicity [16]. Biotechnological platforms have been developed to support the switch from intravenous infusion to SC delivery, using proprietary excipients and proteins, allowing the reduction of ionic strength and hydrophobicity areas of the molecule, thus limiting aggregation when the Ab is highly concentrated.

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