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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

The Importance of Antibody Reagent Validation

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In case more examples are needed, two new reports describe problems associated with antibody reagents:

To educate and inform our members and the broader research community, The Antibody Society has invited leaders in antibody research to reflect on antibody validation in our 10-part webinar series on this topic.

Register now for the next installment:

WEBINAR 9: Getting to Recombinant Antibodies that Guarantee Reproducible Research

February 12, 2020, 10am Eastern Standard Time / 4pm Central European Time, 45 min. webinar + 15 min. chat

Dr. Andrew Bradbury, Specifica, suggests ways out of the validation maze by rigorous molecular identification of recombinant tool antibodies. This achievable goal could eliminate many of the shadowy issues described in this series of webinars.

Register here!

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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“Antibodies to Watch in 2020” is now online!

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This 2020 installment of the annual ‘Antibodies to Watch’ series documents the antibody therapeutics approved in 2019 and in regulatory review in the United States or European Union, as well as those in late-stage clinical studies, as of November 2019*.  At this time, a total of 5 novel antibody therapeutics (romosozumab, risankizumab, polatuzumab vedotin, brolucizumab, and crizanlizumab) had been granted a first approval in either the US or EU, and marketing applications for 13 novel antibody therapeutics (eptinezumab, teprotumumab, enfortumab vedotin, isatuximab, [fam-]trastuzumab deruxtecan, inebilizumab, leronlimab, sacituzumab govitecan, satralizumab, narsoplimab, tafasitamab, REGNEB3 and naxituximab) were undergoing review in these regions, which represent the major markets for antibody therapeutics. Also as of November 2019, 79 novel antibodies were undergoing evaluation in late-stage clinical studies. Of the 79 antibodies, 39 were undergoing evaluation in late-stage studies for non-cancer indications, with 2 of these (ublituximab, pamrevlumab) also in late-stage studies for cancer indications. Companies developing 7 (tanezumab, aducanumab, evinacumab, etrolizumab, sutimlimab, anifrolumab, and teplizumab) of the 39 drugs have indicated that they may submit a marketing application in either the US or EU in 2020. Of the 79 antibodies in late-stage studies, 40 were undergoing evaluation as treatments for cancer, and potentially 9 of these (belantamab mafodotin, oportuzumab monatox, margetuximab, dostarlimab, spartalizumab, 131I-omburtamab, loncastuximab tesirine, balstilimab, and zalifrelimab) may enter regulatory review in late 2019 or in 2020. Overall, the biopharmaceutical industry’s clinical pipeline of antibody therapeutics is robust, and should provide a continuous supply of innovative products for patients in the future.

*Note on key updates through December 20, 2019: 1) the US Food and Drug Administration granted accelerated approval to [fam-]trastuzumab deruxtecan (Enhertu) on December 20, 2019; 2) the US Food and Drug Administration granted accelerated approval to enfortumab vedotin-ejfv (Padcev) on December 18, 2019, bringing the total number of novel antibody therapeutics granted a first approval in either the US or EU during 2019 to 7; 3) the European Commission approved romosozumab on December 9, 2019; 4) the European Medicines Agency issued a positive opinion for brolucizumab; 5) Sesen Bio initiated a rolling biologics license application (BLA) on December 6, 2019; 6) GlaxoSmithKline submitted a BLA for belantamab mafodotin; 7) Macrogenics submitted a BLA for margetuximab; and 8) the status of the Phase 3 study (NCT04128696) of GSK3359609 in patients with head and neck squamous cell carcinoma was updated to recruiting from not yet recruiting.