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Dostarlimab approved by FDA for endometrial cancer

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On April 22, 2021, the U.S. Food and Drug Administration (FDA) granted accelerated approval to Jemperli (dostarlimab) for treating patients with recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing chemotherapy and whose cancers are deficient in their ability to repair DNA inside the cell, as determined by an FDA-approved test. FDA granted dostarlimab Priority Review and Breakthrough Therapy designations for this indication. Dostarlimab (TS-042, GSK4057190A) is an anti-PD-1 humanized IgG4k antibody generated by Anaptysbio under partnership with Tesaro, which was acquired by GlaxoSmithKline in 2019.

Interim analyses of data for patients with mismatch repair (MMR)-deficient endometrial cancer with recurrent or advanced disease that progressed on a platinum doublet regimen enrolled in the Phase 1 GARNET study (NCT02715284) were reported at the European Society for Medical Oncology (ESMO) Virtual Congress in September 2020. Patients received 500 mg of dostarlimab every 3 weeks for the first 4 cycles, then 1,000 mg every 6 weeks until disease progression or discontinuation. The primary endpoints included confirmed objective response rate (ORR) and duration of response (DOR). The ORR was 44.7% in patients with deficient mismatch repair (dMMR) disease and 13.4% in those with MMR-proficient (MMRp) disease. In the dMMR cohort (n = 103), 11 complete responses, and 35 partial responses were observed. Thirteen patients achieved stable disease, while 39 patients experienced disease progression. In the MMRp cohort (n = 142), 3 patients had complete responses, 16 had partial responses, 31 achieved stable disease, and 77 patients experienced progressive disease. At the time of data cutoff, with a median follow up of 11.2 months, the median DOR had not been reached.

Dostarlimab is also being evaluated as a treatment for various types of cancer in early-stage clinical studies, as well as two Phase 3 studies, RUBY and FIRST. The RUBY study (NCT03981796) is evaluating dostarlimab plus carboplatin-paclitaxel versus placebo plus carboplatin-paclitaxel in patients with recurrent or primary advanced endometrial cancer. The primary outcome measure is the progression-free survival (PFS) assessed by an investigator, and the primary completion date is July 2021. The FIRST study (NCT03602859) is a comparison of 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. The primary outcome measure is the PFS and the primary completion date is January 2023.

Need help keeping up to date on US and EU approvals?

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.

Searching for alternatives in anti-EGFR-based therapies: New uses for antibody 528

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Post by Raquel Barroso Ferro, University of Aberdeen

Epidermal growth factor receptor (EGFR) is a well known and validated target for monoclonal antibody (mAb) therapeutics. Three anti-EGFR antibodies are currently marketed, cetuximab, necitumumab, and panitumumab. Cetuximab, a recombinant chimeric (human-mouse) monoclonal antibody (mAb) was the first approved, in February 2004, for treatment of colorectal cancer in patients who failed to respond to irinotecan-based chemotherapy. [1] By binding to EGFR with high affinity, the anti-EGFR antibodies prevent EGF, the ligand to EGFR, binding, and therefore block receptor activation and subsequent pro-survival and proliferation-associated signaling pathways. Therefore, in tumors that depend on this receptor to grow, blocking EFGR can halt tumor progression. This is critical, as patients whose tumors had elevated levels of EGFR/EGF were more likely to have aggressive disease, and therefore a poorer prognosis. [2]

Patients commonly become resistant to anti-EGFR antibody therapies through mutational escape. Cetuximab, necitumumab, and panitumumab bind relatively close epitopes and even share epitope regions on EGFR domain III. [3-5] Whilst a mutation in EGFR can make tumors resistant to one antibody but still susceptible to the remaining two such as in the case of S492R that blocks cetuximab binding but panitumumab remains able [5], there are many mutations that can block a tumor’s susceptibility to all three antibodies simultaneously. [6]

Another anti-EGFR mAb, derived from mouse and known as 528, was first reported in the early 1980s. [7,8] Makabe and colleagues [9] recently reported that, while 528 also binds EGFR domain III, its epitope includes a loop formed by residues 353–362 that is not part of the binding sites of cetuximab, necitumumab, and panitumumab. Thus, tumors that are resistant to all three of the currently available antibodies could in theory be susceptible to 528. Although additional studies are required to accurately deduce the interaction of EGFR and 528, compare 528 to the existing therapies, and assess the effects of various EGFR mutations, these initial findings by Makabe and colleagues are intriguing and represent a worthwhile avenue to explore.

Scientists have also investigated 528’s anti-EGFR binding capabilities in bispecific formats that may have therapeutic potential. Humanized versions of 528’s variable region and the anti-CD3 variable region derived from OKT-3, an immunosuppressant drug, were used to construct a bispecific molecule, hEx3, with the aim of bridging T cells to EGFR on cancer cells, thereby targeting the cancer cells for destruction. [10] This bispecific construct was shown to form functional tetramers. [11] The cytotoxicity of hEx3 could be enhancement by affinity maturation [12], by rearranging the variable domain order [13, 14] and by generating Fc fusions. [14, 15 Taken together, the findings of these studies are intriguing. The simple rearrangement of the heavy and light domains from heavy-light to light-heavy substantially enhanced the cytotoxic anti-tumor activity of the hEx3 diabody, as did the introduction of a LH-HY52W mutation hypothesised to increasing affinity of the 528 variable region and its target, EGFR. Moreover, the engineered molecules had enhanced anti-tumour killing in vivo. [15] This result may be associated with increased valency or perhaps through the reduction of serum clearance, which is currently an obstacle to use of non-native, truncated antibody formats. [16]

Overall, anti-EGFR based antibody therapeutics utilizing 528’s epitope-binding region may present new avenues of attack due to its distanced binding site compared to existing therapies. Importantly, nuanced changes to antibody structures, including simple domain rearrangements and alteration of the amino acid sequence, could translate into substantial changes to efficacy.

References
1.       Wong, SF. (2005). Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. Clin Ther. 47(6): 684-694.
2.       Chen J, et al. Expression and function of the epidermal growth factor receptor in physiology and disease. Physiol Rev. 2016. PMID: 33003261.
3.       Li, S. et al. (2005). Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer. Cell. 7; 301–311.
4.       Bagchi, A. et al. (2018). Molecular basis for necitumumab inhibition of EGFR variants associated with acquired cetuximab resistance. Mol. Cancer. Ther. 17; 521–531. DOI: 10.1158/1535-7163.MCT-17-0575.
5.       Sickmier, E. A. et al. (2016). The panitumumab EGFR complex reveals a binding mechanism that overcomes cetuximab induced resistance. PLoS ONE 11, e0163366. DOI: 10.1371/journal.pone.0163366.
6.       Arena, S. et al. (2015). Emergence of multiple EGFR extracellular mutations during cetuximab treatment in colorectal cancer. Clin. Cancer Res. 21; 2157–2166. DOI: 10.1158/1078-0432.CCR-14-2821.
7.       Kawamoto et al. (1983). Growth stimulation of A431 cells by epidermal growth factor: identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. PNAS. 80 (5) 1337-1341.
8.       Gill GN, et al. Monoclonal anti-epidermal growth factor receptor antibodies which are inhibitors of epidermal growth factor binding and antagonists of epidermal growth factor binding and antagonists of epidermal growth factor-stimulated tyrosine protein kinase activity. J. Biol. Chem. 1984;259:7755–7760. doi: 10.1016/S0021-9258(17)42857-2.
9.       Makabe et al. (2021). Anti-EGFR antibody 528 binds to domain III of EGFR at a site shifted from the cetuximab epitope. Sci. Rep. 11: 5790.
10.   Asano et al. (2006). Humanization of the bispecific epidermal growth factor receptor × CD3 diabody and its efficacy as a potential clinical reagent. Clin Cancer Res. 12(13). DOI: 10.1158/1078-0432.CCR-06-0059.
11.   Asano et al. (2010). Highly enhanced cytotoxicity of a dimeric bispecific diabody, the hEx3 tetrabody. J. Biol. Chem. 285(27); 20844-20849.
12.   Nakanishi, T. et al. (2013) Development of an affinity-matured humanized anti-epidermal growth factor receptor antibody for cancer immunotherapy. Protein Eng. Des. Sel. 26, 113–122.
13.   Asano et al. (2013). Domain order of a bispecific diabody dramatically enhances its antitumor activity beyond structural format conversion: The case of the hEx3 diabody. Prot. Eng. Des. Sel. 26(5): 359-367.
14.   Asano, R. et al. (2014) Rearranging the domain order of a diabody-based IgG-like bispecific antibody enhances its antitumor activity and improves its degradation resistance and pharmacokinetics. MAbs 6, 1243–1254.
15.   Asano et al. (2020). Build-up functionalization of anti-EGFR × anti-CD3 bispecific diabodies by integrating high-affinity mutants and functional molecular formats. Sci. Rep. 10; 4913.
16.   Wu et al. (1996).  Tumor localization of anti-CEA single-chain Fvs: improved targeting by non-covalent dimers. Immunotechnology. 2(1): 21-36. DOI: 10.1016/1380-2933(95)00027-5.

Defying the “inevitable” development of type 1 diabetes

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Post written by Raquel Barroso Ferro, University of Aberdeen

Regular exogenous insulin injections, monitoring food and activity levels, increased risk of developing heart and kidney disease. These are some of the many challenges faced by people with type 1 diabetes (T1D), an autoimmune disease where the body’s own immune cells destroy its insulin-producing beta cells. This chronic condition affects over 540,000 children worldwide according to a leading UK charity, and is the second most common childhood disease in the US after asthma (1). Current estimates place a global increase in incidence of 2-5% every year (2), highlighting the increasing number of individuals having to physically, emotionally, and financially bear this burden and the need to develop therapeutics that can prevent, cure or improve the management of this condition.

Development of drugs that can delay the onset of T1D is ongoing. One such drug is teplizumab (hOKT3 γ1(Ala-Ala)), a humanized anti-CD3 monoclonal antibody that has been engineered to have reduced Fc receptor binding. Teplizumab works by modulating T cells, which are immune cells believed to be key players in the destruction of beta cells (3). Maintaining the remaining activity of the beta cells and enabling self-blood glucose control without the need for exogenous influence is critical to controlling the disease.

Results of a Phase 2 study (TrialNet TN10, NCT01030861) of teplizumab reported in 2019 were very promising (4). This randomized, blinded trial investigated if a single two-week course of treatment with teplizumab could delay or prevent the onset of T1D in high-risk individuals that were without a clinical diagnosis of T1D. The researchers observed that over the course of approximately 7 years (July 2011 to November 2018) teplizumab was able to delay the onset of T1D. Furthermore, this trial provided additional evidence of the importance of the T-cell mediated response for the onset of T1D, suggesting the value of using immunomodulation to affect disease development.

Sims et al. (5) extended the follow-up of participants in the original study, and have now reported that the effects persisted in the initial participants who received teplizumab. The median time to onset of T1D was more than double in participants who received teplizumab compared to those who received the placebo (~5 vs 2 years, respectively). Moreover, they observed improvements in beta cell function and, in some, a partial reversal in the decline of insulin secretion. Despite using a small cohort (total study enrolment = 76 participants) and a single 14-day course of drug, the results of this study form the foundation for exciting work in the future to actively prevent the onset of this lifelong condition whose prevalence only seems to be increasing.

A biologics license application for teplizumab for the delay or prevention of clinical T1D in at-risk individuals is undergoing priority review by the U.S. Food and Drug Administration, and their first action on the application is expected by July 2, 2021. The European Medicines Agency is evaluating a marketing authorization application for teplizumab.

References
1.       Menke et al. (2013). The prevalence of type 1 diabetes in the United States. Epidemiology 2013;24:773-774.
2.       Moobaseri et al. (2020).  Prevalence and incidence of type 1 diabetes in the world: a systematic review and meta-analysis. Health Promot Perspect. 2020; 10(2): 98–115. DOI: 10.34172/hpp.2020.18.
3.       Gaglia J, Kissler S. Anti-CD3 Antibody for the Prevention of Type 1 Diabetes: A Story of Perseverance. Biochemistry. 2019 Oct 8;58(40):4107-4111. doi: 10.1021/acs.biochem.9b00707.
4.       Herold et al. (2019). An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. N Engl J Med 2019; 381:603-613. DOI:  10.1056/NEJMoa1902226.
5.       Sims et al. (2021).  Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals. Science Translational Medicine. 13 (583); eabc8980. DOI: 10.1126/scitranslmed.abc8980.

Triple-negative Breast Cancer Day, March 3, 2021

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On March 3rd each year, the global community affected by and working to treat triple-negative negative breast cancer (TNBC) comes together to raise awareness of this disease. Like all cancers, breast cancer is heterogenous. The triple-negative form of the disease is characterized by the absence of expression of the estrogen and progesterone receptors and lack of amplification of human epidermal growth factor receptor 2 (HER2) on tumor cells, which makes it particularly difficult to treat. Although only ~10-20% of all breast cancer cases, TNBC is particularly aggressive, and occurs more commonly in women younger than age 40, who are African-American, or who have a BRCA1 mutation. The 5-year survival rate is high (91%) if the disease is localized when first diagnosed, but decreases substantially (to 12%) if the tumor has already metastasized.

Due to the lack, or relatively small number, of relevant receptors, TNBC typically does not respond to hormonal therapeutics or agents targeting HER2. Chemotherapy has been the standard of care, although the benefits of this treatment are limited. Recently, however, three monoclonal antibody (mAb) therapies, atezolizumab (Tecentriq, Genentech Inc.), sacituzumab govitecan-hziy (TrodelvyTM, Immunomedics, Inc.), and pembrolizumab (KEYTRUDA, Merck & Co.) were approved by the US Food and Drug Administration (FDA) for TNBC. In addition, numerous other mAbs are in late-stage clinical study for this disease.

Atezolizumab is a humanized IgG1 mAb targeting programmed cell death protein 1 ligand (PD-L1) that was first approved by FDA for treatment of locally advanced or metastatic urothelial carcinoma in 2016. The Fc domain of atezolizumab was engineered by introducing an Asp to Ala change at position 298 in the CH2 domain of each heavy chain. Due to this alteration, the antibody devoid of N-linked oligosaccharides and does not have effector functions. On March 8, 2019, the FDA granted accelerated approval to atezolizumab in combination with paclitaxel protein-bound for adult patients with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] of any intensity covering ≥ 1% of the tumor area), as determined by an FDA-approved test. Approval was based on the placebo-controlled Phase 3 IMpassion130 (NCT02425891) study of 902 patients with unresectable locally advanced or metastatic TNBC who had not received prior chemotherapy for metastatic disease. In patients whose tumors express PD-L1, median progression-free survival was 7.4 months for patients receiving atezolizumab with paclitaxel protein-bound and 4.8 months for those receiving placebo with paclitaxel protein-bound. The objective response rate in patients with confirmed responses was 53% compared to 33% for the atezolizumab and the placebo-containing arms, respectively. Tecentriq is also approved in the European Union for treatment of TNBC.

Sacituzumab govitecan is an antibody-drug conjugate (ADC) comprising a humanized IgG1k antibody targeting TROP-2 fused to the active metabolite of irinotecan (SN-38). On April 22, 2020, FDA granted Trodelvy® an accelerated approval for adults patients with metastatic TNBC who received at least two therapies for metastatic disease. FDA’s approval was based on findings from the pivotal, single-arm clinical trial IMMU-132-01 (NCT01631552) that enrolled 108 previously treated patients with metastatic TNBC. The overall response rate was 33.3% and the median response duration was 7.7 months. Of the patients with a response to sacituzumab govitecan-hziy, 55.6% maintained their response for 6 or more months and 16.7% maintained their response for 12 or more month.

Pembrolizumab is a humanized IgG4 mAb targeting programmed cell death protein 1 (PD-1) that was first approved by FDA for treatment of melanoma in 2014. On November 13, 2020, FDA granted accelerated approval to pembrolizumab in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test. FDA’s approval was based on results from the Phase 3 KEYNOTE-355 study (NCT02819518) of patients with locally recurrent unresectable or metastatic TNBC, who had not been previously treated with chemotherapy in the metastatic setting. Median progression-free survival was 9.7 months in the pembrolizumab plus chemotherapy arm and 5.6 months in the placebo arm.

Other ADCs and antibodies that target PD-1 or its ligand (PD-L1) are undergoing evaluation in late-stage clinical study of TNBC patients, including the anti-HER2 ADC trastuzumab deruxtecan (Enhertu); anti-PD-L1 avelumab (Bavencio) and TQB2450; and anti-PD-1 serplulimab and toripalimab. More information about TNBC and antibody therapeutics for this disease can be found in these reviews:

Nagayama A, Vidula N, Ellisen L, Bardia A. Novel antibody-drug conjugates for triple negative breast cancer. Ther Adv Med Oncol. 2020 May 11;12:1758835920915980. doi: 10.1177/1758835920915980.

Won KA, et al. Triple‑negative breast cancer therapy: Current and future perspectives. Int J Oncol. 2020. PMID: 33174058.

Keep up to date on US and EU approvals all year by visiting our website!

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.

Rare Disease Day, February 28, 2021

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On or about the last day of February each year, the rare disease community comes together to raise awareness of these conditions. In the US, any disease affecting fewer than 200,000 people (1 per ~1,650 people) is considered rare, while a disease is defined as rare in Europe when it affects fewer than 1 in 2,000 people. There are more than 7,000 rare diseases, and these collectively affect ~ 25-30 million Americans. Information about specific rare diseases can be found in the National Organization for Rare Disorders’ Rare Disorders Database and the National Institutes of Health’s Genetic and Rare Diseases Information Center.

In the US, the Orphan Drug Act passed by Congress in 1983 incentivizes the development of drugs to treat rare diseases. Similar programs in Europe, Japan, as well as other countries, also allow other regulatory agencies to grant ‘orphan drug’ designations.  Hundreds of drugs have been approved for the treatment of rare diseases, including numerous antibody therapeutics, although substantial medical need still remains. Antibody therapeutics recently approved for rare diseases include:

  • Caplacizumab (Cablivi), a treatment for acquired thrombotic thrombocytopenic purpura, which is a rare blood clotting disorder.
  • Crizanlizumab (Adakveo), indicated to reduce the frequency of vaso-occlusive crisis, which is a painful complication of sickle cell disease that occurs when blood circulation is obstructed by sickled red blood cells.
  • Teprotumumab (Tepezza), indicated for 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.
  • Inebilizumab (Uplizna) and satralizumab (Enspryng), treatments for neuromyelitis optica spectrum disorder, which is a rare autoimmune disorder of the central nervous system that primarily damages the optic nerve(s) and spinal cord, causing blindness, muscle weakness and paralysis.
  • Evinacumab (Evkeeza), a treatment for homozygous familial hypercholesterolemia, which is a genetic condition that causes severely high cholesterol.
  • Ansuvimab (Ebanga) and the triple antibody cocktail of atoltivimab, maftivimab, and odesivimab (Inmazeb) for the treatment for Zaire ebolavirus (Ebolavirus) infection.
  • Naxitamab (DANYELZA®) for the treatment of relapsed or refractory high-risk neuroblastoma in the bone or bone marrow.

More information about these antibody therapeutics, including target, format and year of approval, can be found here.

Other antibody therapeutics for rare diseases are in late-stage clinical studies and may be approved soon, including:

  • Garetosmab, which is undergoing evaluation as a treatment for fibrodysplasia ossificans progressive (FOP), an ultra-rare genetic disorder characterized by the progressive replacement of soft tissue, such as muscles, tendons, and ligaments, by bone, a process known as heterotopic ossification. Regeneron plans regulatory submission(s) for garetosmab for FOP in 2021.
  • Mirvetuximab soravtansine, which is undergoing evaluation as a treatment for ovarian cancer. ImmunoGen anticipates the submission of a biologics license application for accelerated approval of mirvetuximab soravtansine for ovarian cancer during the second half of 2021.
  • KN046, which is undergoing evaluation as a treatment for thymic carcinoma. Alphamab Oncology has announced that the Phase 2 clinical trial (NCT04469725) of KN046 to treat thymic carcinoma will support their plan to submit marketing applications for KN046 to China’s National Medical Products Administration and the US Food and Drug Administration in 2021.

More information about antibody therapeutics in late-stage studies can be found in ‘Antibodies to Watch in 2021‘.

Keep up to date on US and EU approvals all year by visiting our website!

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.