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Register for the “Delivering therapeutic mAbs for COVID-19” webinar on May 20th!

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Accelerating the timeline from biopharmaceutical discovery to clinical evaluation has long been a focus for industry. For potentially life-saving therapies, the earliest clinical testing enables accelerated pivotal trials and maximum patient benefit. In 2020, novel discovery and development strategies have rapidly evaluated antibodies for passive immunization or treatment of COVID-19, employing CMC timelines from lead identification to clinic cut in half. These strategies combine the latest advances in established platforms with acceptance of higher business risk or costs, while ensuring no increased patient risk.

But speed to clinic for COVID-19 antibody therapies must be matched by speed to launch and immediate ramp-up in supply to realize a meaningful impact on the global pandemic. Parallel workflows must be initiated at the onset for process and product development as well as cGMP manufacturing. The initial focus on speed to clinic complements a slower approach to development of the most productive commercial cell line, efficient manufacturing process and optimal drug product configuration. Rapid production of initial clinical material followed by pivotal and commercial production arising from cell line, process and formulation optimization emphasizes the importance of product comparability, structure/function knowledge and appropriate control strategies. Meanwhile, scale-up and technology transfer to large manufacturing facilities starts before the first patient is dosed. These strategies impact the program’s technical and regulatory risk profiles, staff and capital resourcing, and set up trade-offs in multiple areas.

This case study describes the development history of a COVID-19 antibody, reviewing CMC milestones from lead identification to preparation of the commercial license application as well as plans for post-licensure opportunities, all in one year.

Click here to register for this free webinar!

Congratulations to the Antibody Engineering & Therapeutics Europe poster competition winners!

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To recognize the research activities of promising student/postdoctoral fellows, The Antibody Society sponsors a competition each year for members who submit posters for Antibody Engineering & Therapeutics Europe. This conference will be held virtually June 8-10, 2021.
Our judges select the best work based on originality, relevance and perceived impact on the field of antibody research and development.

 

Winners receive:

1) Complimentary registration to attend the conference and pre-conference sessions;
2) An opportunity to give a short oral presentation of their work in one of the conference sessions;
3) A lovely crystal award.

We are pleased to announce the winners of the 2021 poster competition:

Ms. Suchada Niamsuphap, Australian Institute for Bioengineering and Nanotechnology.

Poster title: Development of antibody delivery systems against intracellular targets

and

Dr. Vaishali Verma, University of Delhi South Campus.

Poster title: ImPACT: Immunization-free Phage-based Antibody Cloning Technology

More about these winners and the winners of past competitions can be found here.

Please join us for the virtual Antibody Engineering & Therapeutics Europe conference on June 8-10 to hear their presentations!

Society members receive a 15% discount on the registration fee. Contact us at membership@antibodysociety.org for the code.

Loncastuximab tesirine granted first approval by FDA for large B-cell lymphoma

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On April 23, 2021, the  US Food and Drug Administration (FDA) granted accelerated approval to loncastuximab tesirine-lpyl (Zynlonta, ADC Therapeutics SA) for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma. This marketing application was granted priority review and orphan drug designation by FDA. The review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

Loncastuximab tesirine (ADCT-042) is an antibody-drug conjugate composed of an anti-CD19 humanized IgG1k antibody conjugated via a linker to pyrrolobenzodiazepine-dimer toxin that induces the killing of CD19-expressing malignant B cells.

The BLA submission was supported by data from the open-label, single-arm Phase 2 LOTIS 2 study (NCT03589469), which evaluated the safety and efficacy of loncastuximab tesirine for the treatment of patients with relapsed or refractory DLBCL following ≥2 lines of prior systemic therapy. A total of 145 patients received loncastuximab tesirine as an intravenous infusion over 30 minutes on Day 1 of each cycle (every 3 weeks) at a dose of 150 μg/kg for 2 cycles, then 75 μg/kg for subsequent cycles for up to one year or until disease progression, unacceptable toxicity, or other discontinuation criteria. The primary outcome measure is the overall response rate (ORR). Positive initial data from LOTIS 2 were presented during the virtual 25th Annual Congress of the European Hematology Association. The ORR was 48.3% (70/145 patients), the complete response rate was 24.1% (35/145 patients), and the median duration of response was 10.25 months. The toxicity profile was manageable and no new safety concerns were identified.

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.

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.