INTRODUCTION:

Primary Immunodeficiency (PI) refers to a miscellaneous group of disorders characterized by poor or absent function in one or more components of the immune system. Over 130 different disorders are identified so far, with new disorders continually being recognized. Most PIDs causes from inherited defects in immune system development and/or function; however, acquired forms have also been described. PIDs are distinct from secondary immune deficiencies which will result from other causes, like viral or bacterial infections, malnutrition, or treatment with drugs that induce immune suppression.

The clinical presentation of Primary Immunodeficiency is very variable as most disorders involve increased susceptibility to infection. In fact, many PIDs cause as “routine” infections (often of the sinuses, ears and lungs) and, therefore, may go undetected within the primary immune system. The accurate and correct diagnosis of those disorders requires a high number of suspicion and specialized testing. Human immunoglobulin is an entrenched replacement therapy for patients with primary immunodeficiency disorders (PIDs).

Recombinant human hyaluronidase (rHuPH20) is an enzyme present in our body that temporarily digests hyaluronan in the skin interstitial making it possible for large volumes of fluid or drug solutions to be infused and absorbed subcutaneously. ENHANZE® drug delivery technology is a significant technology for the proprietary rHuPH20 Human recombinant enzyme that facilitates the subcutaneous delivery of co administered therapeutics.

Primary Immune Deficiencies:

Primary Immune deficiencies (PID) are an outsized group of defects of immunity, and have many heterogeneous features, which might include abnormally frequent or severe illness from common organisms, opportunistic infections, autoimmune phenomena, and allergic disease. Amidst all the classes of PID with defective or absent T-lymphocyte function like severe combined immunodeficiency (SCID), viral infections are frequent and infrequently mortifying¹. Cytomegalovirus (CMV), herpes (EBV), and adenovirus (ADV) are the foremost common cases of viral-associated mortality in children with SCID².

Pathophysiology:

The infection vulnerability and other clinical features of an immunodeficiency appears from the absence or altered function of one or more gene products. Each of minutiae of those aspects of all disorder rely on the biochemical roles of those gene products and the cells or tissues within which they're expressed. The environmental factors and products of interacting genes and their polymorphisms also play a task. for many immunodeficiencies, it's necessary to keep a knowledge about the biochemical, cellular, organic, and systemic consequences of a specific defect. Some samples of a motivating phenomenon in immunodeficiency: syndromes having identical or very similar clinical and immunologic phenotypes may arise from disrupted function of molecular entities that interact with each other to sub serve one biochemical function or pathway. XLA was one in every of the primary immunodeficiencies to be defined at the molecular level. The BTK tyrosine kinase is critical for transducing a symbol from the B cell surface immunoglobulin receptor (Fig. 2). Within the pre-B cell, this receptor consists of an immunoglobulin μ heavy chain, the heterodimeric surrogate light chain containing lambda 5 (λ5) and Vpre B, and the signal transducers Ig alpha (Igα), and Ig beta (Igβ). Within the cytoplasm, BTK interacts with other kinases, and with so-called scaffold or adaptor proteins that serve to juxtapose other signaling intermediates, permitting activation to proceed downstream along the molecular pathway³.

Figure 1: A simplified diagram summarizing the relationships of several molecules and their associated with agammaglobulinemia.

Hypogammaglobulinemia:

Hypogammaglobulinemia is one of the major kind hallmarks of patients with Primary Antibody Deficiency (PAD) and the main manifestation is recurrent bacterial infections, predominantly occurring in the respiratory and gastrointestinal tracts. The infections are usually caused by pyogenic bacteria with Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aureginosae being the foremost common species⁴. Unlike patients with T lymphocyte deficiencies who have increased susceptibility to opportunist infections, patients with antibody deficiencies don't have problems with fungal or viral pathogens, except patients with X-linked agammaglobulinemia (XLA), who are liable to enteroviruses and should develop chronic enteroviral encephalomyelitis. Patients are usually freed from infection until the latter a part of the primary year of life, as passively acquired IgG from the mother decreases to below protective levels. If given replacement gamma globulin therapy and prophylactic antibiotics most patients with antibody deficiency can lead normal lives. Early diagnosis and adequate therapy are the keys to survival and a much better quality of life. Delays in diagnosis and/or inadequate management may result in permanent organ damage (e.g., bronchiectasis or bronchiolitis obliterans) or death from overwhelming infection⁵.

Figure 2: Algorithm approach of molecular diagnosis in patients with hypogammaglobulinemia

Hyaluronic acid:

Hyaluronic acid (HA) is a naturally occurring mucopolysaccharide found in all living organisms. It has a structural feature that is made from several thousands of carbohydrates long. When it binds to water it becomes a stiff viscous consistency like structure which is like a "Jello". One of its functions within the body is to bind water and to lubricate movable parts of the body, like joints and muscles. Its consistency and tissue-bound nature allow it to be used in skin-care products as an excellent moisturizer. Hyaluronic acid is one among the foremost hydrophilic (water-loving) molecules in nature and may be described as nature’s moisturizer.

Figure 3: Structure of hyaluronan

Synthesis:

According to Lee and Spicer (in 2000) naturally, mucopolysaccharide HA is derived by a category of integral membrane proteins defined as hyaluronan synthases (HS), of which vertebrates have three varieties of proteins: HAS1, HAS2, and HAS3. An integral membrane protein could also be a molecule (or assembly of proteins) that in most cases spans the biological membrane with which it's associated (especially the plasma membrane) or which, is sufficiently embedded within the membrane to stay with it during the initial steps of biochemical purification (in contrast to peripheral membrane proteins)⁶.

Degradation:

The enzymatic degradation of Hyaluronic Acid in mammals causes form three kinds of enzymes: hyaluronidase, beta-d-glucuronidase, and β-N-acetyl-hexosaminidase. The degradation products of hyaluronan, oligosaccharides and low relative molecular mass hyaluronan, exhibit pro-angiogenic properties (Mio and Stern, 2002)⁷.

Applications:

FDA approved Hyaluronic acid which can be used via intra-articular injection to treat osteoarthritis of the knee. A review showed that the standard of studies supporting this use was mostly poor, with general absence of serious benefit, and intra-articular injection of mucopolysaccharide could possibly cause adverse effects.

Dry, scaly skin, like that caused by atopic eczema, could also be treated with skin lotion containing sodium hyaluronate as its active ingredient. Hyaluronic acid has been utilized in various formulations to make artificial tears to treat dry eye.

Hyaluronic acid may be a common ingredient in skin care products. Hyaluronic acid is employed as a dermal filler in face lift its typically injected using either a classic sharp needle or a micro-cannula. In some cases, mucopolysaccharide fillers end in a granulomatous foreign body reaction⁸.

Hyaluronidase:

Hyaluronidase enzyme has been successfully implemented over the past 60 years in ophthalmic surgery and now being utilized in dermatological surgery as well as in other surgical disciplines and in making subcutaneous infusions. The main function of this enzyme is to de-complex Hyaluronic Acid. When Hyaluronidase is used as an adjuvant, it enhances the diffusion capacity and bioavailability of the drug infused. Therefore, in local anesthetics this enzyme is used as a diffusion capacity enhancer as well increasing the analgesic efficacy, and therefore the anesthetized area particularly within the first minutes following injection, resulting in diminished post- and intraoperative pain. The management of HA-filler-associated complications in aesthetic medicine is as off-label use which is considered the gold standard for⁹.

Recombinant Human Hyaluronidase (rhuph20):

The family of hyaluronidase enzymes hydrolyzes one major constituent of the interstitial barrier known as hyaluronic acid (a glycosaminoglycan). Human Recombinant Hyaluronidase is a highly purified recombinant human hyaluronidase. It is under investigation as a neoadjuvant to facilitate local interstitial drug delivery as well as increase bioavailability. It lowers the viscosity of the interstitial barrier by breaking down hyaluronic acid¹⁰.

Enhanze™ Technology:

Partners with Injectable Biologics and Drugs:

EDP is an investigational product that allows co-mixing of the partner therapeutic with rHuPH20 at the clinical site (simulating a co-formulated product) to allow quick initiation of early stage trials. This can shorten the time to entry into dose-finding Phase 1 trials compared with developing a co formulation (single vial) prior to the initiation of clinical trials. Co-formulation efforts generally, occur in parallel with the early trials to support pivotal Phase 3 studies¹¹.

Figure 4: Representation of Bioavailability Preclinical Model study

HYQVIA:

As part of a combination therapy, rHuPH20 was first approved in 2013 in the EU for use with human immunoglobulin infusion (IgG [immune globulin 10%]) for the treatment of primary immunodeficiency (PI) as HyQvia (Shire Pharmaceuticals)¹². Approval followed in the US in 2014 under the name HYQVIA (U.S. Food and Drug Administration, 2012)¹³.

Figure 5: Comparative study between The Adverse effects of HyQvia Infusion and Local IVIG

Before starting HYQVIA:

· Have or had any kidney, liver, or heart problems or history of blood clots because HYQVIA can make these problems worse.

· Have IgA deficiency or a history of severe allergic reactions to IgG or other blood products.

· Are pregnant, trying to become pregnant or are breast feeding.

· Should not be taken HYQVIA if,

· Patient is allergic to IgG, hyaluronidase, other blood products, or any ingredient in HYQVIA¹⁴.

Application of rhuph20 in marketed products:

In addition to HYLENEX® recombinant, rHuPH20 is approved in more than 50 countries for use in co-formulation with two different anticancer therapies, trastuzumab and rituximab (marketed as Herceptin® SC and RITUXAN HYCELA®/RITUXAN® SC/MabThera® SC, respectively), and is administered sequentially with human immunoglobin for primary immunodeficiency (marketed as HyQvia®/HYQVIA®).

Products under development:

The most advanced of the developmental partnerships is with daratumumab (DARZALEX®; Janssen), the primary approved monoclonal antibody for the treatment of multiple myeloma targeting CD38, an antigen highly expressed on multiple myeloma cells. The ongoing open-label Phase 3 trial (NCT03277105) aims to demonstrate the non-inferiority of daratumumab SC to daratumumab IV in terms of overall response rate and plasma conc.through daratumumab levels in patients with multiple myeloma. The results from this trial are expected in 2020. In addition, Alexion Pharmaceuticals is utilizing the ENHANZE drug delivery technology to develop a next-generation Subcutaneous infusion formulation of ALXN1210 (ALXN1210 + rHuPH20, designated as ALXN1810), an investigational long-acting C5 complement inhibitor monoclonal antibody in augmentation for the treatment of paroxysmal nocturnal hemoglobinuria (Alexion Pharmaceuticals I, 2017, 2018). Halozyme is also being undertaken by Bristol-Myers Squibb which is a global collaboration to develop subcutaneously administered immuno-oncology medicines using the ENHANZE drug delivery technology. Included among those medicines is nivolumab (OPDIVO®), which is currently approved in the US to treat 10 types of cancer via a 30-min IV infusion.

ENHANZE drug delivery technology works on the principle of rHuPH20, a patented purified recombinant human hyaluronidase PH20. Hyaluronidases have been used to increase the penetration and diffusion of injected drugs or fluids since the 1940s. rHuPH20 facilitates the route of administration changes (enabling IV therapies to be administered subcutaneously) and can optimize the dosing of SC therapies. Co-administration of rHuPH20 with combination with subsidiary products can overcome administration time and volume barriers associated with existing therapeutic formulations and may reduce the stress on patients and healthcare providers compared with IV formulations. Moreover, rHuPH20 minimizes the adverse effects and immunogenicity associated with the animal-derived hyaluronidases. rHuPH20 is currently approved by the FDA which can increase the absorption and dispersion of SC drugs (HYLENEX recombinant) and is available in various countries in combination with three approved partner products (RITUXAN HYCELA/RITUXAN SC/MabThera SC and HyQvia/ HYQVIA, Herceptin SC).¹⁵

Proprietary product candidates target the matrix pegph20:

Hyaluronan targeting PEGPH20 is a unique investigational approach to Cancer Treatment¹⁶. PEGPH20 (Pegvorhyaluronidase alfa) is a novel formulation of a naturally occurring enzyme which is the PEGylated variant of Recombinant human hyaluronidase enzyme, rHuPH20. The Pegvorhyaluronidase also works in the same mechanism as Recombinant Human Hyaluronidase which temporarily degrades hyaluronan (HA), which is a naturally occurring glycosaminoglycan or chain of natural sugars that are common throughout the body and can accumulate in the tumor micro-environment of certain solid tumor types.¹⁷

Mechanism of action:

· Hyaluronic Acid abundant halos found on many types of aggressive tumors (breast, prostate, pancreatic)

· PEGPH20 collapses Hyaluronic Acid dependent pericellular glory halos on tumor cells

· Modulates resistance to chemotherapy

Others:

1. Insulins: Combination of rHuPH20 for prandial diabetes therapy

2. Bisphosphonates: Combination of rHuPH20 for osteoporosis

3. Chemo phase: Combination of rHuPH20 with Mitomycin for bladder cancer

4. PEGPH20: Pegylated HA targeting rHuPH20 expressing tumors

5. HTI-501: Novel Matrix degrading enzyme for dermatological therapy

CONCLUSION:

Extracellular matrix is a significant barrier for the delivery of several drugs which limits the pharmacokinetic parameters and injection volumes. To overcome such difficulties various novel drug delivery technologies are progressively being commercialized such as ENHANZE® drug delivery system. It involves the studies of patients with primary and secondary immunodeficiency syndromes who received human immunoglobulin with recombinant human hyaluronidase. A large, neat, comparative trials with appropriate statistical methodology were also wisely preferred with relevant pharmacodynamic and pharmacokinetic data analysis. The wide applicability range of this technology is to boost both injection volumes and bioavailability in a fruitful way.

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Received on 10.07.2020 Modified on 15.09.2020

Research J. Pharm. and Tech. 2021; 14(8):4504-4508.

DOI: 10.52711/0974-360X.2021.00783