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FDA issues guidance on conducting clinical trials during the COVID-19 pandemic

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In these challenging times, the biopharmaceutical industry, government agencies, as well as academic and non-profit organizations, are working toward the development of antibody therapeutics and vaccines for the treatment and prevention of infection by SARS-CoV-2, the virus that causes COVID-19. The Antibody Society is currently compiling information on these efforts, which will soon be posted on our website and distributed via email to our members. Many existing antiviral treatments are also being re-purposed in the fight against the virus.

The Society is an authoritative source of information on antibody therapeutics in the clinical pipeline. The COVID-19 pandemic, however, may delay ongoing clinical studies that are evaluating the safety and efficacy of therapeutics for other diseases. In a March 18, 2020 press release, the U.S. Food and Drug Administration (FDA) notes that challenges may arise from quarantines, site closures, travel limitations, interruptions to the supply chain for the investigational product, or other considerations if site personnel or trial subjects become infected with SARS-CoV-2. These challenges may lead to difficulties in conducting the clinical trials. Protocol modifications may be required, and there may be unavoidable protocol deviations due to COVID-19.

Information about FDA’s guidance for industry, investigators and institutional review boards conducting clinical trials during the coronavirus (COVID-19) pandemic can be found here.

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Molecular Biology Can Improve Antibody Drug Developability

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Contributed by  Nick Hutchinson, FUJIFILM Diosynth Biotechnologies

The discovery and development of antibody therapeutics often adheres to a series of stages starting with target identification and progressing through lead generation, lead optimization, then testing in preclinical and clinical studies. Molecular biologists engineer antibodies during lead generation and optimization to improve a range of characteristics, including antibody specificity and potency, or to reduce immunogenicity and the rate of elimination from the body (1).

Next-generation antibody biopharmaceuticals include bispecifics, glyco-engineered antibodies and antibody-fusion proteins with complex architectures. While drug development scientists may use antibody engineering techniques to generate candidates with very desirable or improved functional properties, at the same time, these can alter the biochemical, biophysical and in vivo properties of the antibody candidate, which can be detrimental to the overall target product profile (2). Engineering antibodies to improve their functional properties is frequently performed without consideration for the subsequent developability, including manufacturability, of the molecule. These issues are then often identified at a relatively late stage in the discovery process, after substantial resources have been invested in the molecule and, therefore, can have a real financial impact on drug development companies that may be being kept alive by funding from investors.

Ideally, antibody therapeutics should be capable of being manufactured with high productivity and at high quality with low protein heterogeneity. From a developability perspective, it is preferable if they express to high titer from the mammalian cell expression system and are stable during production storage and delivery (1). Some antibody candidates can exhibit a propensity to partially unfold, revealing hydrophobic patches that are more normally buried inside the molecule. Once revealed, the patches can interact with one another, leading to aggregation. Other liabilities that reduce developability include low solubility, unstable amino acids, clipping and antibody fragmentation (1). These can be sufficiently severe that projects can be cancelled due to poor toxicology data and concerns around whether the candidate can be safely administered to patients during clinical trials.

One solution, advocated by investigators from Roche (2), is to assess developability during antibody drug discovery. Their workflow incorporates two separate assessments, the first following the initial candidate screening and selection and the second following humanization and re-engineering, but before the selection of the clinical lead. During the first phase of the assessment, complementarity-determining regions are analysed in silico for potential liabilities such as degradation sites. This can be followed by studies on stressed samples, with samples incubated at elevated temperatures for two weeks. Stable candidates can progress to the next stage or drug development scientists can use humanization and protein re-engineering to remove the identified liabilities. The second phase, which follows humanization, again employs in silico tools but evaluates the whole humanized molecule and assesses potential hotpots where post-translational modification, charge variations or degradation might occur. Researchers then perform a second stress test for the most likely or detrimental liabilities. During this phase, they can include tests for self-interaction and aggregation, such as apparent hydrophobicity by hydrophobic interaction chromatography, thermal stability by dynamic light scattering (DLS), protein-protein self-interaction by DLS and viscosity at high concentration by DLS with latex beads (2).

Other groups have gone further, and not only select for candidates with properties that limit manufacturing and storage risks, but also apply molecular engineering techniques in order to improve manufacturability proactively. For example, in 2019, a team from AstraZeneca described manufacturing challenges they encountered during downstream purification of an antibody that was undergoing liquid-liquid phase separation (3). This in turn resulted in the need for longer mixing times that can be damaging for proteins, yield losses, increases in pressure during processing and misleading analytical results from in-process samples. The team attempted to resolve the problem by optimize the bioprocessing conditions, but there were still substantial limitations to large-scale manufacturing. To fix the problem, they used in silico homology modelling and charged-patch analysis to identify problematic residues, and this ultimately lead them to substitute charged residues with those with a neutral or opposite charge. Their research showed that these substitutions minimized electrostatic interactions and allowed them to engineer a variant that maintained antigen-binding affinity, but eliminated the liquid-liquid phase separation behaviour.

The molecular engineering of therapeutic antibodies is allowing development of candidates with ever improved functional properties. However, researchers should consider, where possible, the impact of this engineering on the biochemical and biophysical characteristics of the molecule, which can have a negative effect on the developability of lead candidates. Incorporating screens for developability during drug discovery workflow can help eliminate candidates with liabilities that will prevent them from being successful drugs. The more sophisticated developers of antibody therapeutics are cleverly applying molecular biological techniques to improve the stability and manufacturability of their monoclonal antibody leads.

(1) Chiu, M.L. & Gilliland, G.L. (2016) Engineering antibody therapeutics. Current Opinions in Structural Biology, 38: 163-173.

(2) Jarasch, A., Koll, H., Regula, J.T., Bader, M., Papadimitriou, A. & Kettenberger, H. (2015) Developability assessment during the selection of novel therapeutic antibodies. Journal of Pharmaceutical Sciences, 104:1885-1898.

(3) Du, Q., Damschroder, M., Pabst, T.M. Hunter, A.K., Wang, W.K. & Luo, H. (2019) Process optimization and protein engineering mitigated manufacturing challenges of a monoclonal antibody with liquid-liquid phase separation issues by disrupting inter-molecule electrostatic interaction. MAbs, 11 (4): 789-802.

The Antibody Society is an authoritative source of information about antibody therapeutics development. We are pleased to provide original posts and news summaries on our homepage, as well as semi-monthly summaries of recent news to our members.  Archived news from 2019 can be found in the Web Resources section of the Society’s website.

Bispecific antibodies come to the fore

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Bispecific antibodies are a versatile class of targeted therapeutics designed to bind two different sites, which can be located on a single antigen or on two antigens. Although bispecific antibodies were conceptualized ~60 years ago, various challenges associated with protein engineering, stability and manufacturing delayed their wide-spread development. However, as of 2020, numerous validated platforms, i.e., those that have produced bispecific clinical candidates, are readily available (1). Using these platforms, the commercial clinical pipeline has grown to over 100 bispecific antibodies, ranging from tandem single-chain variable fragments (scFv) to full-length immunoglobulins with dual variable domains. Substantial growth in the pipeline has occurred only relatively recently, though. During the early 2010s, bispecific antibodies comprised less than 10% of the total number of antibody therapeutics entering clinical study per year, but this number rose to 25% by 2018. Reflecting the general success of antibody therapeutics, the entry of all types of new, innovative antibody candidates into clinical study also grew substantially during this period, from 63 on average during the early 2010s to over 140 in 2018.

As is the case for the overall pipeline of antibody therapeutics, the majority of bispecific antibodies that have entered clinical study recently are being evaluated as treatments for cancer. Among these, the most common approach involves guiding T cells to cancer cells via a bispecific antibody, which binds to a tumor-associated antigen on a cancer cell and CD3 on T cells. Bispecifics that use this mechanism of action comprise ~45% of the pipeline. Of the T-cell engaging bispecifics now in the clinic, B-cell maturation antigen is the tumor-associated antigen most frequently targeted, followed by CD20, CD33, CD123 and prostate-specific membrane antigen. Of the bispecific antibodies in the clinical pipeline that do not re-direct T cells, the most frequent targets are programmed cell death 1 (PD1) and its ligand (PD-L1), human epidermal growth factor 2 (HER2) and vascular endothelial growth factor (VEGF). The most frequently paired targets are HER2/HER2 (different epitopes), PD1/CTLA4, PD-L1/4-1BB, VEGF/Ang-2 and VEGF/Delta-like ligand 4. Immune checkpoint proteins are frequent targets, including PD1 paired with LAG3, ICOS and TIM3, as well as PD-L1 paired with LAG3 and CTLA4.

The increased number of antibody therapeutics in the commercial clinical pipeline is due, at least in part, to the relatively high approval success rate of these molecules. Since 2014, at least 6 antibody therapeutics have been approved in either the US or European Union each year, and the number of approvals in 2020 is expected to exceed that of the all-time high of 13 approvals set in 2018 (2). Overall, antibody therapeutics have a 22% approval success rate, defined as the percentage of molecules that successfully transitioned from Phase 1 to approval of all that entered Phase 1 (3). For each clinical phase transition, the lowest rates are for the transition from Phase 1 to 2 (69%) and from Phase 2 to 3 (45%). So far, bispecific antibodies are very similar to the broader category of antibody therapeutics in their Phase 1 to 2 (71%) and Phase 2 to 3 (46%) transition rates. Since so few bispecific antibodies have reached Phase 3 or been approved, there is insufficient data for the calculation of meaningful transition rates for Phase 3 to regulatory review and regulatory review to approval. Despite this, the favorable early phase transition rates are good news for bispecific antibody developers.

In addition to success rates, the length of time required for clinical development and regulatory review is a key drug development metric. Typically for antibody therapeutics, 4-6 years is considered a relatively short period, ~ 8 years is about average, and a period of 10-12 years is considered lengthy. As with success rates, a meaningful average development period for bispecific antibodies is not available because only 3 have been approved (emicizumab, catumaxomab, blinatumomab), and 2 of these are likely not representative of bispecifics currently in clinical development. Of the 3 approved products, emicizumab, a humanized IgG4 targeting Factor IXa and Factor X approved for hemophilia, proceeded through clinical development to approval the fastest (~5.25 years), and it is most similar in structure to a canonical IgG antibody. In contrast, blinatumomab took the longest (~13 years), and it is the most dissimilar to a canonical IgG, which is typically includes human or humanized protein sequence. Blinatumomab is a tandem scFv composed of murine protein sequence with such a short half-life (2.1 hours) that continuous intravenous dosing is required for efficacy.

Because most bispecific antibodies in the commercial pipeline entered clinical studies in just the past few years, marketing approvals, if granted, may not occur for at least 4-5 years. However, two bispecific antibodies, tebentafusp and faricimab, qualify as ‘Antibodies to Watch’ (2) with late-stage clinical study primary completion dates in 2020. Tebentafusp, which is composed of a soluble T cell receptor fused to an anti-CD3 scFv (4), is being evaluated in a pivotal Phase 2 study with a primary completion date in July 2020. Faricimab is a bispecific CrossMAb (5) targeting VEGF-A and Ang-2 undergoing evaluation in several Phase 3 studies with primary completion dates in September 2020. Tebentafusp and faricimab are being studied as treatments for uveal melanoma and diabetic macular edema, respectively. Results from the clinical studies, which will help determine whether the molecules advance to regulatory review, may be available in the second half of 2020.

In summary, bispecific antibodies are entering clinical studies in record numbers, with most developed for cancer. Data available to date indicates that these molecules have similar early clinical phase transition rates, and the potential for similar development periods, compared with canonical IgG antibodies. Data discussed here will be updated and presented at PEGS Boston in the “Clinical Validation of Platforms” session of the “Engineering Bispecific Antibodies” track on Friday May 8, 2020.

1.      Labrijn AF, Janmaat ML, Reichert JM, Parren PWHI. Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 2019;18(8):585–608. doi:10.1038/s41573-019-0028-1

2.      Kaplon H, Muralidharan M, Schneider Z, Reichert JM. Antibodies to watch in 2020. MAbs. 2020;12(1):1703531. doi:10.1080/19420862.2019.1703531

3.      Kaplon H, Reichert JM. Antibodies to watch in 2019. MAbs. 2019;11(2):219–238. doi:10.1080/19420862.2018.1556465

4.      Damato BE, Dukes J, Goodall H, Carvajal RD. Tebentafusp: T cell redirection for the treatment of metastatic uveal melanoma. Cancers (Basel). 2019;11(7):971. Published 2019 Jul 11. doi:10.3390/cancers11070971.

5.      Klein C, Schaefer W, Regula JT. The use of CrossMAb technology for the generation of bi- and multispecific antibodies [published correction appears in MAbs. 2018 Nov 13;11(1):217]. MAbs. 2016;8(6):1010–1020. doi:10.1080/19420862.2016.1197457

Two new antibody therapeutics enter regulatory review

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Biologics license applications (BLA) for tanezumab and dostarlimab have been submitted by Pfizer and GlaxoSmithKline, respectively.

Tanezumab is a humanized IgG2 antibody that selectively targets nerve growth factor. It has a novel mechanism compared to opioids and other analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs), and, in studies to date, tanezumab has not demonstrated a risk of addiction, misuse or dependence. FDA granted Fast Track designation for tanezumab for the treatment of osteoarthritis pain and chronic lower back pain. During a Q4 earnings conference call on January 28, 2020, Pfizer announced that it completed a marketing application submission for tanezumab in December 2019. This submission was done in close collaboration with the FDA, and it includes the 2.5 mg dose in moderate-to-severe osteoarthritis patients. A decision on the application may occur by the end of 2020. The submission was confirmed by development partner Eli Lilly. Tanezumab is also being evaluated in Phase 3 study of patients with cancer pain due to bone metastasis who are taking background opioid therapy.

Dostarlimab (TSR-042) is a humanized IgG4 antibody that binds with high affinity to the PD-1 receptor and effectively blocks its interaction with the ligands PD-L1 and PD-L2. Dostarlimab is being developed by Tesaro (a division of GlaxoSmithKline) for the treatment of solid tumors, including endometrial cancer that could be classified as microsatellite stable (MSS/75%) or microsatellite instability-high (MSI-H/25%). GlaxoSmithKline’s BLA is for dostarlimab as second-line treatment of recurrent endometrial cancer. Tesaro is also evaluating dostarlimab as a treatment for ovarian cancer in the Phase 3 FIRST study (NCT03602859). This study will compare platinum-based therapy with dostarlimab and niraparib versus standard of care platinum-based therapy as first-line treatment of Stage III or IV non-mucinous epithelial ovarian cancer.

Tanezumab and dostarlimab are now queued for a possible first approval in 2020 along with 13 other antibody therapeutics:

  1. Isatuximab, a humanized IgG1 targeting CD38 for multiple myeloma
  2. Inebilizumab, a humanized IgG1 targeting CD19 for neuromyelitis optica and neuromyelitis optica spectrum disorders
  3. Eptinezumab, a humanized IgG1 targeting CGRP for migraine prevention
  4. Leronlimab, a humanized IgG4 targeting CCR5 for HIV infection
  5. Sacituzumab govitecan, a humanized IgG1 antibody-drug conjugate targeting TROP-2 for  triple-negative breast cancer
  6. Satralizumab, a humanized IgG2 targeting IL-6R for neuromyelitis optica spectrum disorder
  7. Narsoplimab, a human IgG4 targeting MASP-2 for hematopoietic stem cell transplant-associated thrombotic microangiopathies
  8. Tafasitamab, a humanized IgG1 CD19 for diffuse large B-cell lymphoma
  9. REGNEB3, mixture of 3 human IgG1 targeting the Ebola virus for Ebola virus infection
  10. Naxitamab, a humanized IgG1 targeting GD2 for high-risk neuroblastoma and refractory osteomedullary disease
  11. Oportuzumab monatox, a humanized scFv immunotoxin targeting EpCAM for bladder cancer
  12. Belantamab mafodotin, a humanized IgG1 ADC targeting B-cell maturation antigen for multiple myeloma
  13. Margetuximab, a chimeric IgG1  targeting HER2 for HER2+ metastatic breast cancer

The Antibody Society maintains a comprehensive table of approved monoclonal antibody therapeutics and those in regulatory review in the EU or US. The table, which is located in the Web Resources section of the Society’s website, can be downloaded in Excel format. Information about other antibody therapeutics that may enter regulatory review in 2020 can be found in ‘Antibodies to watch in 2020’.

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First approval for teprotumumab-trbw (Tepezza)

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On January 21, 2020, the U.S. Food and Drug Administration (FDA) approved Tepezza (teprotumumab-trbw) for the treatment of adults with thyroid eye disease, which is associated with an outward bulging of the eye that can cause eye pain, double vision, light sensitivity or difficulty closing the eye. Teprotumumab, a human IgG1 antibody targeting insulin growth factor 1 receptor, was granted Fast Track, Breakthrough Therapy and Orphan Drug designations by the FDA. Positive data from both Phase 2 (NCT01868997) and Phase 3 (OPTIC, NCT03298867) studies were reported by Horizon Pharma. In the randomized, placebo-controlled OPTIC study, teprotumumab met the study’s primary endpoint, which was a responder rate of ≥ 2 mm reduction of proptosis (bulging) in the study eye (without deterioration in the fellow eye) at Week 24. Data from the OPTIC study showed that 82.9% of patients receiving teprotumumab were proptosis responders compared to 9.5% of patients receiving placebo at Week 24 (p<0.001). All secondary endpoints in the study were also met.

The Antibody Society maintains a comprehensive table of approved monoclonal antibody therapeutics and those in regulatory review in the EU or US. The table, which is located in the Web Resources section of the Society’s website, can be downloaded in Excel format. Information about other antibody therapeutics that may enter regulatory review in 2020 can be found in ‘Antibodies to watch in 2020’.

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