In “Antibodies to Watch in 2022”, Drs. Janice Reichert, Alicia Chenoweth and Silvia Crescioli will discuss key events in antibody therapeutics development that occurred in 2021 and forecast events that might occur in 2022. The COVID-19 pandemic continued to pose challenges and opportunities to the healthcare system, but companies forged ahead with development plans, resulting in record numbers of antibody therapeutics in late-stage clinical studies and in regulatory review. Globally, regulatory agencies approved a record number of novel antibody-based products, including anti-SARS-CoV-2 antibodies. The speakers will provide details of 2021 events and trends in the development of antibody therapeutics projected for 2022.
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
Author: Nick Hutchinson, Fujifilm Diosynth Biotechnologies
The demand for antibody and antibody-related therapeutics continues to increase.  The United States Food and Drug Administration has approved ~ 100 antibody therapeutics for a wide range of treatments. Nearly 600 antibody drugs are in clinical trials,  with ~75 of these in pivotal Phase 2 or Phase 3 studies.
Small or even virtual companies are developing many of these molecules. Technical teams working within these organizations must understand the activities needed to successfully commercialize the drugs. One critical activity is establishment of production strategies capable of supplying the material requirements of pre-clinical development, toxicology studies, clinical trials and then, if successful, market demand.
Patients cannot benefit from life-saving medicines if the drug’s launch is delayed due to lack of the material required for each phase of development. Furthermore, companies that miss clinical milestones suffer from delayed investments, thus reducing the opportunity to reach the clinic in a timely manner and capture market share, which lowers future revenues.
Many start-up biotech firms have a laser-like focus on the pre-clinical development of their antibody candidates, but sooner or later they must consider a manufacturing strategy that enables pre-clinical or clinical programs to stay on track.
Is manufacturability an obstacle to development?
One question drug developers should consider is the extent to which the manufacturability of the candidate is likely to be problematic and jeopardise material supply. Many of the standard, full-length antibodies have well-understood properties and are relatively easy to manufacture, allowing timely delivery to the clinic. However, there is an increasing number of modalities within this product class,  e.g., bispecifics, Fc-fusions and antigen-binding fragments, which may present additional production challenges. These can include challenges such as low expression from cell lines suitable for use in manufacturing, poor stability during purification processes or the need for non-standard analytical methods.
One company I spoke to, for example, knew that they needed to increase the productivity of their cell cultures from below 0.5 g/L to greater than 3 g/L in order for the product to be commercially viable. Another company developing a monoclonal antibody explained that they needed a titer of ~ 10 g/L to ensure production efficiency was sufficiently high to allow them to be price competitive. A third company found that the isoelectric point of their Fc-fusion molecule was relatively low and they needed a tailored purification process for their product.
Companies developing standard IgG1, IgG2 or IgG4 products can leverage manufacturing platforms.  These allow production of different monoclonal antibodies with the required quality specifications and at high productivity with little process development. They offer a significant time- and cost-saving over the alternative, i.e, developing new processes for each new candidate. Companies with a pipeline of products may choose to invest in their own manufacturing platform, but, for many early-stage biotech companies it makes little sense to spend investors’ cash on production assets when there is considerable uncertainty around the likely success of a program. For this reason, many will outsource process development and manufacturing to a contract development and manufacturing organization (CDMO), many of whom will have their own established platform processes.
Early material supplies of antibody candidates
Cell line development scientists can generate stable, clonal cell banks derived from a production-ready host cell line in as little as 10 weeks following transfection. Cell cultures with transfectant pools can produce tens to hundreds of grams of material in as little as eight weeks following transfection. Scientists developing antibody therapeutics can use this antibody for their pre-clinical activities and initial formulation development experiments. In our experience, even at the pre-clinical stage, the drug development process can consume substantial amounts of material. Accurately determining material requirements at this stage will help ensure sufficient antibody is available.
Preclinical material supply might be met with bench-scale bioreactors, but we have worked on programs where the material requirements were sufficiently large that a 200-L mammalian cell culture run was needed, even though the cell line gave a high titer. This clearly demonstrated the utility of having a platform process because no additional process development on either the bioreactor conditions or the purification steps was needed. Expert developers of cell lines know that their host cell line will grow to high cell density under their platform conditions, and will select clones that combine high productivity with the desired product quality profile using high-throughput screening technologies.
Process development scientists operating platform processes typically allocate time, which would previously have been dedicated to manufacturing development, to the refinement of operating parameters and studies of manufacturing robustness that increase the likelihood of that full-scale production lots will be successfully released.
Supplying Toxicology and Early Clinical Material
Pilot-scale batches allow companies to predict large-scale manufacturing performance and refine scale-dependant process parameters. Companies often use material from the pilot-scale batch for toxicology work, stability studies and for generating reference standard, against which the first batch for clinical use can be released. It generally takes 6 – 8 months to reach this stage from the start of cell line development, yielding hundreds of grams of antibody, if not more.
For many companies, the demand for clinical-grade drug, manufactured to current Good Manufacturing Practices (GMP), can be met using bioreactors no larger in volume than 2000-L. The initial batch can be released within 12-14 months from the start of cell line development. Each batch can supply between 1 to 10 kilograms of antibody.
Modern, high-throughput manufacturing facilities provide enormous amounts of capacity such that with a robust, high-titer cell line no further scale-up may be required and firms can commercialize their product within the same facility they used for clinical lots. Others elect to scale-up still further to large-scale stainless steel manufacturing facilities, especially if the market demand is high and the overall process productivity is modest. More recently, firms are considering going to market with manufacturing processes that utilize smaller bioreactors operated in a continuous, perfusion mode. We believe such processes can yield over 15 kg of antibody from a 500-L bioreactor over a 4-week period. Deciding which approach to adopt is never easy because of uncertainties around factors such as dose requirements, overall market demand and competitive pressures. Experienced CDMOs will support customers through this decision-making process and will be able to provide invaluable advice.
In conclusion, many small biotech companies with new antibody drug assets can mitigate risks to drug development and commercialization timelines by thoroughly understanding the material supply requirements for preclinical, toxicology and clinical studies. Once they know this, they can determine how the need can be met by manufacturing organizations during process development and GMP production operations as part as an over-arching strategy for product commercialization.
On August 23, 2019 GlaxoSmithKline announced positive headline results from the pivotal DREAMM-2 study of the antibody-drug conjugate belantamab mafodotin (GSK2857916) for multiple myeloma. The two-arm study met its primary objective and demonstrated a clinically meaningful overall response rate with belantamab mafodotin in the patient population. The safety and tolerability profile was consistent with that observed in DREAMM-1, the first time in human study of belantamab mafodotin. Data from the DREAMM-2 study will be the basis for regulatory filings starting later this year.
• Belantamab mafodotin is a humanized anti-B-cell maturation antigen monoclonal antibody that is afucosylated and conjugated to the microtubule-disrupting agent monomethyl auristatin-F.
On August 29, 2019 AbbVie announced that MERU (NCT03033511), a Phase 3 trial evaluating the antibody-drug conjugate rovalpituzumab tesirine (Rova-T) as a first-line maintenance therapy for advanced small-cell lung cancer, demonstrated no survival benefit at a pre-planned interim analysis for patients receiving Rova-T as compared with placebo. The overall safety profile was generally consistent with that observed in previous studies. The MERU trial is being closed, and the Rova-T research and development program has been terminated. AbbVie will move forward prioritizing other development programs within its oncology pipeline.
• Rovalpituzumab tesirine is an antibody-drug conjugate composed of a humanized monoclonal antibody, dipeptide linker, and pyrrolobenzodiazepine dimer toxin with a drug-to-antibody ratio of 2. The antibody component targets cancer-stem cell-associated delta-like protein 3.
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The Antibody Society maintains a comprehensive table of approved mAb therapeutics and those in regulatory review in the EU or US. Located in the ‘Web Resources’ section of our website, the list is updated regularly and can be downloaded in Excel format. Information about antibody therapeutics that may enter regulatory review in 2019 can be found in ‘Antibodies to watch in 2019’.
The Antibody Society’s presentation, “Antibodies to watch and more: Early and late-stage clinical development trends” was given on June 26, 2019, as part of KNect365’s Digital Week.
In this presentation, Dr. Janice Reichert, Executive Director of the Society, provided an update to the Antibodies to Watch in 2019 paper, which was published in mAbs in February. She gave a brief summary of antibody therapeutics approved January to June this year in either the US or EU, and antibodies in regulatory review and those that might enter regulatory review soon. Dr. Reichert also discussed trends for nearly 160 antibodies that entered clinical study from January 2018 to mid-June 2019, including use of different antibody formats and mechanisms of action, and she provided specifics regarding the popular and less trendy targets.
Click here to download the presentation and learn which antibodies are the ones to watch in 2019 and 2020!
Like this post but not a member? Please join!
The Antibody Society maintains a comprehensive table of approved mAb therapeutics and those in regulatory review in the EU or US. Located in the ‘Web Resources’ section of our website, the list is updated regularly and can be downloaded in Excel format.