Feliza Mirasol is the science editor for 

Feliza Mirasol

Editor's note: this story was originally published on 

Belgium-based contract development and manufacturing organization (CDMO) White Raven and Cytiva announced on March 19, 2024, that White Raven is installing Cytiva's SA25 Aseptic Filling Workcell at its fill/finish site. This installation completes White Raven’s drug product platform and will increase its manufacturing efficiency. The site is expected to be good manufacturing practice (GMP)-compliant with the new system by the end of 2024.

SA25 is an integrated gloveless robotic isolator that eliminates the need for operator intervention, according to a company press release. The system is designed to provide an optimal aseptic process and comprises a standardized flexible filler that is capable of producing vials, syringes, and cartridges in batch sizes ranging from 100 to up to 20,000 units. The system has a fill-volume range of 0.2 mL – 50 mL. Because it is a closed robotic system, it reduces the risk of product contamination. It also allows for changeover between drug formats within a 45-minute timeframe.

Ludovic Brellier, president, Biotechnology Integrated Solutions and Business Operations, Cytiva. Image courtesy of Cytiva.

“White Raven recognizes that by replacing a human operator with a robotic gloveless isolator, they can remove the biggest risk for contamination—ensuring they are taking the right steps to protect customers’ high value drug products. The need for greater standardized solutions to improve this process is a trend we are seeing across the industry,” Ludovic Brellier, president of Biotechnology Integrated Solutions and Business Operations, Cytiva, says.

White Raven offers a range of formulation services adapted to clinical batches and is capable of working with mixing volumes as low as 50 mL and up to 20 L. The CDMO also offers GMP formulation and aseptic filling of injectable drugs for pre-clinical, clinical, and orphan drugs. White Raven employs single-use consumables over the full aseptic filling process to also reduce contamination risk.

The company is part of Cytiva’s aseptic filling user group, which is a group that works closely with Cytiva to collaborate on best practices, such as system validation and operations. White Raven expects the installed workcell to complete a site acceptance test by mid-2024, prepping the site for GMP readiness by end of the year.

Considerations for improving aseptic operations in the bio/pharma industry are an ongoing exercise for manufacturers. Automation technologies have been a major solution in this area. However, in one sense, automated aseptic processes can be seen as “often playing catch up to the new tools that are being developed,” according to Dan Strange, chief technology officer at Cellular Origins, in a 

 video interview (1). “These consumables and equipment … have been fundamentally designed for manual processes … and that's very hard to automate. It's … straightforward for a manual operator to automate, but it's hard for traditional automated systems to handle that,” Strange noted in the interview.

Drug Digest: Improving Aseptic Processing and Manufacturing Needs

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CDMO White Raven aims to reduce contamination risk and gain the capability to handle multiple product formats with the installation of Cytiva’s SA25 Aseptic Filling Workcell.

White Raven to Increase Manufacturing Efficiency with Cytiva’s Aseptic Filling Workcell

FDA has approved Lenmeldy (atidarsagene autotemcel) from Orchard Therapeutics, making it the first approved gene therapy for treating children with pre-symptomatic late infantile, pre-symptomatic early juvenile, or early symptomatic early juvenile metachromatic leukodystrophy (MLD) in the United States. Following the March 18, 2024, approval, AGC Biologics announced that it will be manufacturing the therapy at its Milan, Italy, site.

According to a FDA press release, MLD is a debilitating, rare genetic disease that affects the brain and nervous system caused by a deficiency of the arylsulfatase A (ARSA) enzyme. This deficiency leads to a buildup of sulfatides in the cells, which causes damage to the central and peripheral nervous system, leading to a loss of motor and cognitive function and early death. MLD is estimated to affect one in every 40,000 individuals in the US, and there is no cure for it. Currently, treatment typically focuses on supportive care and management of symptoms.

Peter Marks, director, FDA’s Center for Biologics Evaluation and Research (CBER). Image courtesy of FDA.

“This is the first FDA-approved treatment option for children who have this rare genetic disease,” said Peter Marks, director of FDA’s Center for Biologics Evaluation and Research (CBER), in the press release. “We remain committed to advancing scientific and regulatory principles that enable the efficient development and review of safe, effective and innovative products that have the potential to change patients’ lives.”

Lenmeldy, derived from the patient’s own hematopoietic stem cells (HSCs), is a one-time, individualized single-dose infusion. The patient’s HSCs are collected and genetically modified to include functional copies of the ARSA gene. The modified cells are then transplanted back into the patient where they engraft within the bone marrow and supply the body with ARSA enzyme-producing myeloid cells. The enzyme helps break down the build-up of sulfatides and may stop the progression of MLD. Prior to treatment with Lenmeldy, patients must undergo high-dose chemotherapy to removes cells from the bone marrow that can then be replaced with the modified HSCs, according to the FDA release.

“This approval represents important progress in the advancement and availability of effective treatments, including gene therapies, for rare diseases,” said Nicole Verdun, director of the Office of Therapeutic Products in CBER. 

Nicole Verdun, director, Office of Therapeutic Products, CBER. Image courtesy of FDA.

The application for Lenmeldy received priority review, orphan drug, rare pediatric disease, and regenerative medicine advanced therapy designations.

Following Lenmeldy’s approval, contract development and manufacturing organization (CDMO), AGC Biologics, announced that its Milan, Italy, site has received clearances from both US and European regulators and can now use approved commercial processes to supply patients with the gene therapy. The company will begin commercial manufacturing for the lentiviral vector and genetically modified cell drug product (DP) for Lenmeldy at the site.

“It is wonderful to see Orchard Therapeutics reach this goal. This accomplishment is a strong proof point of our commitment at AGC Biologics to collaborating directly with developers to meet rigorous regulatory standards and achieve the best possible results for our partners,” said Patricio Massera, CEO, AGC Biologics, in a March 18, 2024 company press release.

According to the company press release, the Milan site has become the only CDMO site to receive FDA clearance to commercially produce this gene therapy for US patients. AGC Biologics stated in the release that the FDA approval is “the culmination of a partnership that started in 2018 with Orchard Therapeutics, which also includes guiding the product through commercial approval by the European Commission (EC) in 2021 [under the European brand name Libmeldy] (1). AGC Biologics’ Milan site is uniquely connected to this product’s full lifecycle, as the facility and our scientific teams partnered with each company that owned this treatment’s IP [intellectual property] over the [p]ast 20 years to help advance it from research and development stages to this DP commercial milestone.”

Luca Alberici, general manager of AGC Biologics Milan, stated in the release, “We congratulate Orchard for reaching this important stage. Our team has had the privilege of supplying every clinical milestone for Lenmeldy and are glad to see it reach FDA approval. I am proud of the work of the Milan team.This demonstrates our unique ability to collaborate on technical processes to deliver groundbreaking treatments to patients worldwide. This approval makes our site one of the rare few in the viral vector and genetically modified cells field that has commercial manufacturing authorization from two of the world’s leading regulatory authorities."

"AGC Biologics has played a pivotal role as a strategic partner throughout the clinical development and commercial scale-up of atidarsagene autotemcel, which helped facilitate regulatory approvals in Europe and the US," added Nicoletta Loggia, chief technical officer of Orchard Therapeutics, in the company press release. "Utilizing our … commercial HSC gene therapy manufacturing platform, we have consistently met the demands for drug product production since the European launch in early 2021. This has enabled us to provide treatment to patients from three continents, including Europe on a commercial basis, the Middle East through treatment abroad programs, and the US, under compassionate use. With the recent US approval, we are excited to further expand access to this vital therapy for eligible children with early-onset MLD."

1. Orchard Therapeutics. Orchard Therapeutics Receives EC Approval for Libmeldy for the Treatment of Early-Onset Metachromatic Leukodystrophy (MLD). Press Release, Dec. 21, 2020.

FDA's approval makes Orchard Therapeutics' Lenmeldy (atidarsagene autotemcel) the first gene therapy approved to treat pediatric metachromatic leukodystrophy in the US.

FDA Greenlights Orchard Therapeutics' Gene Therapy for Children's MLD; AGC Biologics Selected for Manufacturing

On March 13, 2024, Japan=based Ricoh Company, a digital services company, and Ireland-based ERS Genomics announced that they have entered into a non-exclusive licensing agreement in the United States and Japan that gives Ricoh access to clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) genome editing technology patents managed by ERS Genomics.

CRISPR/Cas9 has been shown to be a breakthrough gene editing technology as it enables relatively easy modification of targeted genome sequences. It has become an essential tool in drug discovery research and has application across other fields, according to Ricoh in a company press release. The CRISPR technology is “

” that UK Medicines and Healthcare products Regulatory Agency’s (MHRA’s) approval of Casgevy in November 2023 “caused quite a stir in both the medical and pharmaceutical worlds” (1,2). Alongside FDA’s approval of Casgevy in December 2023, the regulatory authorities’ approvals mark a significant 

 in the biopharma industry (3,4). Casgevy is the first therapeutic based on CRISPR/Cas9 gene-editing technology to be approved by regulatory authorities anywhere in the world (4).

As part of Ricoh’s strategy with its recent moves, the company is aiming to predict the mechanism of action of drug candidates for patients with varied genetic backgrounds. The goal is to improve the speed and efficiency with which messenger RNA (mRNA) is designed; the company plans to achieve this goal by combining certain core technologies with the CRISPR/Cas9 genome editing technology. In 2022, the company completed the acquisition of Baltimore, Md.-based Elixirgen Scientific (5), whose core technologies enable the rapid and efficient differentiation of human induced pluripotent stem cells as well as the design, production, and management of mRNA.

By manipulating the genetic editing of cells to enhance or diminish specific functions, it thus becomes possible to create highly reliable disease models, including models for rare diseases. Ricoh expects that such an advancement will lead to shorter drug development timelines and increased success rates, according to the company press release. Meanwhile, following through on its acquisition of Elixirgen Scientific, Ricoh has been expanding the application areas for that company’s technology through its expertise in digital and artificial intelligence technologies.

New Medicines, Markets, and Manufacture: CRISPR for Sickle Cell Disease and β-thalassemia

 online, Nov. 30, 2023.
2. Vertex Pharmaceuticals. Vertex and CRISPR Therapeutics Announce Authorization of the First CRISPR/Cas9 Gene-Edited Therapy, CASGEVY (exagamglogene autotemcel), by the United Kingdom MHRA for the Treatment of Sickle Cell Disease and Transfusion-Dependent Beta Thalassemia. Press Release, Nov. 16, 2023.
3. FDA. FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease. Press Release, Dec. 8, 2023.
4. Mirasol, F. 

Milestone Approval to Steady Stream, Gene Editing Revs Up

 (2), 16–19,25.
5. Ricoh. Ricoh to Strengthen Support for Drug Discovery Services Using mRNA. Press Release, May 17, 2022.

Ricoh aims to create novel disease models for R&D using ERS Genomics’ CRISPR/Cas9 genome editing technology.

Ricoh and ERS Genomics Enter License Agreement for CRISPR/Cas9 Technology

ProBioGen, a Germany-based contract development and manufacturing organization, announced on  March 13, 2024, that it has entered into services and license agreements with Mapp Biopharmaceutical to develop a cell line for an afucosylated antibody that targets Marburg virus (MARV) infection. The companies will leverage ProBioGen's GlymaxX technology to adjust the afucosylation levels of antibody and enhance its therapeutic potential.

Under the agreement, ProBioGen will use its expertise in cell-line development, including its proprietary DirectedLuck transposase system and GlymaxX technology, to enhance the candidate’s antibody-dependent cellular cytotoxicity (ADCC). According to the company in a press release, “ADCC enhancement is a key strategy for improving therapeutic antibody-drug efficacy.”

The GlymaxX technology is designed to optimize antibody activity. It does so by enhancing antibody-mediated cell killing of cancerous or infected cells. The technology is based on the stable introduction of a gene into producer cells; the gene encodes for an enzyme that blocks the cells' fucose biosynthesis pathway and, thus, the formation of fucose. As a result, no fucose is added in the antibody-producer cells to the antibody's N-linked carbohydrate part. The absence of fucose in antibodies is known to significantly enhance ADCC, ProBioGen stated in its press release.

GlymaxX can be applied to both novel or already existing antibody producer cell lines as well as to entire antibody expression and discovery platforms. ProBioGen stated that “GlymaxX does not negatively affect cellular productivity or other product characteristics. Furthermore, a GlymaxX cell line can be flexibly used to produce differently fucosylated products, depending on the upstream process: in fucose-free medium the antibody is literally afucosylated.”

"We are excited to collaborate with [Mapp Biopharmaceutical] in the development of a cell line for an afucosylated antibody targeting MARV infection, utilizing our GlymaxX technology," said Volker Sandig, chief scientific officer, ProBioGen, in the press release. "This again confirms the versatility of our technology which is broadly used for cancer therapeutics but can also make a meaningful impact in the fight against life-threatening infections."

The Marburg virus poses a significant public health threat, and there is urgent need for advanced therapies to treat it, which this collaboration aims to address. MARV infections cause severe and often fatal illness. The development of an antibody offers a promising route for treatment. In this case, by reducing fucose levels in the antibody's glycan structure, ProBioGen’s GlymaxX technology can enhance the antibody’s effector functions, which can potentially improve its overall efficacy against MARV infection.

The project is being funded in whole or in part by federal funds from the US Department of Health and Human Services, the Administration for Strategic Preparedness and Response, Biomedical Advanced Research and Development Authority (BARDA), under contract number 75A50122C00076 (1).

"We are pleased to partner with ProBioGen to develop a cell line to produce our afucosylated antibody to treat MARV infection," said Ronald Aimes, vice-president, Development—Marburg, Mapp Biopharmaceutical, in the press release. "This collaboration exemplifies our shared commitment to addressing unmet medical needs and underscores the potential of combining our capabilities to deliver innovative and impactful biopharmaceutical solutions for infectious diseases."

Mapp Biopharmaceutical specializes in the infectious disease space within the biopharma industry. The company has received funding from BARDA to advance the development of MBP091, a single monoclonal antibody (mAb) therapeutic for treating Marburg virus disease. This would be the first mAb therapy to specifically treat MARV infections, according to the company in the press release.

1. HHS Office of the Assistant Secretary for Preparedness and Response (ASPR). 

www.highergov.com/contract/75A50122C00076/

Mapp Biopharmaceutical will use ProBioGen’s GlymaxX technology for the development of an afucosylated antibody against Marburg virus infection

Mapp Biopharmaceutical Teams Up with ProBioGen and to Develop Antibody Against Marburg Virus Disease

Domain Therapeutics (Domain), a clinical-stage biopharmaceutical company developing innovative drug candidates in immuno-oncology that target G protein-coupled receptors (GPCRs), entered into a manufacturing agreement with Chime Biologics, a contract development and manufacturing organization. Chime Biologics will produce Domain’s regulatory T cell (Treg)-depleting anti-CCR8 antibody candidate, DT-7012, Domain announced in a March 12, 2024 press release.

Under the agreement, Chime Biologics will ensure stable cell line development (CLD) and manufacturing services for the candidate to support clinical trials in strategic countries. Chime Biologics operates a global modular facility that employs single-use bioprocessing technology. According to the company, this facility meets international current good manufacturing practice standards and holds proven audit track records.

The candidate, DT-7012, is a novel anti-CCR8 comprising monoclonal antibody (mAb)-depleting tumor-infiltrating Tregs, which are major immunosuppressive cells. The company stated, in the press release, that, “Treg depletion with anti-CCR8 mAb has demonstrated a unique anti-tumor potency as a monotherapy” and noted that, “DT-7012 has a proven best-in-class potential compared to other clinical-stage CCR8 antibodies, paving the way for effective GPCR-targeting immunotherapies, aiming to activate antitumor immunity for cancer patients unresponsive to other treatments”.

The company expects to start Phase I clinical studies of the candidate in early 2025 for solid tumors. In mid-2025, it expects to start Phase I clinical studies in cutaneous T-cell lymphoma.

Domain nominated DT-7012 in June 2023 (1). The company choose this candidate because of its unique ability and potential as a monotherapy to cure cancer in preclinical studies. The company expects the candidate to achieve a position that will enable its fast-track development and accelerated market access. According to the company, DT-7012 is able to preserve CCR8-modulation capacity in the presence of high concentrations of CCR8 in the tumor microenvironment. It also has the ability to recognize different forms of CCR8 that have different post-translational modifications (1).

“We look forward to progressing this strategic partnership, which combines Domain’s leading anti-CCR8 antibody candidate with Chime Biologics’ CLD-to-commercial manufacturing expertise, contributing to the development of DT-7012 for various cancers,” said Jimmy Wei, president of Chime Biologics, in a company press release.

“We’re thrilled to collaborate with Chime Biologics, a great scientific and manufacturing expert, to advance DT-7012, our leading anti-CCR8 candidate, to the next development stage. This new GPCR-targeting immunotherapy has immense potential to unlock the immune system’s cancer fighting abilities and help patients globally. At Domain, we prioritize precision research and innovation and embrace new partnerships with organizations that share our vision and passion to advance immuno-oncology,” said Stephan Schann, chief scientific officer of Domain Therapeutics, in the release.

In addition to DT-7012, Domain’s pipeline of GPCR-targeting immunotherapies also includes:

PAR2 NAM antagonist (DT-9045): a small-molecule candidate expected to begin a Phase I study by mid-2025

EP4 receptor antagonist (DT-9081): a small-molecule candidate expected in an ongoing Phase I ascending dose study

A2a/A2b antagonist (M1069): a small-molecule candidate being developed in partnership with Merck KGaA that is in an ongoing Phase I ascending dose study.

1. Domain Therapeutics. Domain Therapeutics Announces Nomination of Best-in-class CCR8 Antibody Candidate, DT-7012, Further Strengthening Its Unique Portfolio of GPCR-targeting Immunotherapies. Press Release, June 29, 2023.

In a new manufacturing pact, Chime Biologics will produce DT-7012, Domain Therapeutics' antibody candidate for treating cancer that will soon be entering Phase I studies.

Chime Biologics to Manufacture Novel Antibody Cancer Immunotherapy for Domain Therapeutics

The European Medicines Agency (EMA) announced on March 4, 2024 that it has validated two marketing authorization applications (MAAs) submitted by AstraZeneca and Daiichi Sankyo for their antibody drug conjugate (ADC) candidate, datopotamab deruxtecan (Dato-DXd). The parallel applications are seeking indications in two types of cancer: locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) and unresectable or metastatic hormone receptor (HR)-positive, HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer in patients who have progressed on and are not suitable for endocrine therapy and who have received at least one additional systemic therapy.

The agency’s validations confirm that the MAAs are complete, and the agency can now commence the scientific review process, which is to be carried out by EMA’s Committee for Medicinal Products for Human Use. The two applications are based on data from two pivotal Phase III clinical trials (TROPION-Lung01 and TROPION-Breast01), which were presented during two Presidential Symposia at the 2023 European Society for Medical Oncology Congress.

Datopotamab deruxtecan is an ADC specifically engineered to target TROP2, a protein broadly expressed in several solid tumors, including the majority of NSCLC and HR-positive, HER2-negative breast cancer cases. High TROP2 expression is associated with increased progression of tumors and poor survival. Currently, there is no approved TROP2-directed ADC for treating lung cancer, according to an AstraZeneca press release.

Datopotamab deruxtecan was discovered by Daiichi Sankyo and is being jointly developed by AstraZeneca and Daiichi Sankyo. The companies entered into a global collaboration for the ADC in July 2020 (1). AstraZeneca has rights to the product except in Japan, where Daiichi Sankyo maintains exclusive rights. Meanwhile, Daiichi Sankyo is responsible for the manufacturing and supply of the ADC.

“Our ambition is for datopotamab deruxtecan to improve upon and replace conventional chemotherapy in the treatment of multiple cancer types. Today’s dual validation of our applications in lung and breast cancers brings this potential medicine a meaningful step closer to redefining treatment expectations for patients with two of the most common cancers in Europe,” said Susan Galbraith, executive vice-president, Oncology R&D, AstraZeneca, in the press release.

“The EMA validation is an important first step toward bringing this TROP2-directed antibody drug conjugate to eligible patients in Europe with nonsquamous lung cancer and HR-positive, HER2-negative breast cancer. This news builds on our recent regulatory progress in the [United States], where our lung cancer application has been accepted and our breast cancer application is underway, underscoring our commitment to changing the standard of care by developing new medicines to help as many patients worldwide as possible," said Ken Takeshita, global head, R&D, Daiichi Sankyo, in the press release.

Regulatory submissions for the ADC in lung cancer and breast cancer are also underway in the US and globally.

1. AstraZeneca. AstraZeneca and Daiichi Sankyo Enter Collaboration to Develop and Commercialize New Antibody Drug Conjugate. Press Release, July 27, 2020.

EMA has validated two MAAs submitted by AstraZeneca and Daiichi Sankyo for datopotamab deruxtecan in two types of cancer.