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Funding the Development of Antibody Innovations, Part 2: Business Angels and Venture Capitalists

May 26, 2021 by The Antibody Society

By Tom Burt (Partner, Sofinnova Partners) & Nick Hutchinson (BSG Lead, Mammalian Cell Culture, FUJIFILM Diosynth Biotechnologies)

Antibody scientists with exciting technologies typically require substantial amounts of capital to develop their ideas and turn them into products that can be marketed. In the case of therapeutic antibodies, this can take many years and cost millions if not billions of dollars. In our first post on raising finance to support antibody innovations, we described why scientists are excited about raising finance at the current time (1). In this second post, we explore possible sources of funding for newly formed antibody companies at the very beginning of the funding cycle.

Venture capitalist (VCs) firms have traditionally been significant sources of funding for start-up biotech companies because they are undeterred by the risk that an individual company may not generate a return due to the challenges of product development in this sector. In order to generate a return on their investments, VCs back numerous start-ups in the hope that a minority will win big. However, for most scientists attempting to commercialize the fruits of their research labors, VCs are probably not the first port of call when attempting to raise funds. Biotech start-ups commonly rely on pre-seed funding in the form of government grants, bank loans, technology transfer funding from universities and even family or friends.

Business Angels are also sources of early finance. These are often individual, or syndicates of wealthy, private individuals that invest their own money in sectors that they know and understand. They typically make smaller investments than VC, usually up to $2 million, but small companies can often obtain the funds sooner. Angel investors are often interested in being involved in the project and are able to provide mentoring and access to useful networks in addition to the funding they bring.

Start-up biotechs use this seed funding to protect their intellectual property and progress their idea sufficiently such that VCs or other partners will become interested in the technology. Fortunately, in the past few years the cost of research infrastructure has gone down, allowing start-up companies to make greater progress with their ideas prior to reaching out to the VC community. Low rent lab-space is now more commonly available, suppliers provide more convenient ways to access equipment, and entrepreneurial scientists can outsource more routine studies and testing to contract research organizations.

Antiverse, a UK-based biotech start-up, recently announced it had raised £1.4 million [US$2m] to fund the development of its Artificial Intelligence-powered antibody discovery technology for accelerating antibody drug development by accurately predicting antibody-antigen binding. The company believes their platform will enable the development of antibody drugs for difficult targets associated with cancer, and heart and lung diseases. It will use the money to further develop the platform, to build a new laboratory in Cardiff, Wales, and to recruit specialist machine-learning engineers, laboratory scientists and structural biologists. The funding was raised from The Development Bank of Wales and a syndicate of Angel Investors.

While the levels of pre-seeding funding might not match that provided by VCs, some founding scientists see a benefit in taking maximum advantage of investments that allow them to retain greater control.

Tom Burt of Sofinnova Partners says, “To truly scale a start-up requires quantums of growth capital that can really only feasibly be provided by VCs. Beyond the necessary capital, VCs are also helpful to emerging companies in more qualitative ways, given their accumulated experience of financing other similar enterprises. VCs can contribute by attracting talent to Board and Management-level positions who increase the probability of success through sage advice on all areas of development.”

“In addition, the VC’s network can be invaluable in forging connections with potential pharma and biotech partners as well as investors and bankers for assistance with further financings. While the founder can expect some loss of control, VCs are typically minority investors looking to work collegially with other stakeholders to improve outcomes,” he continues.

In our next post, we’ll look at the first two rounds of financing that VCs provide to antibody start-up companies and we’ll introduce the concept of the cross-over fund, a relatively new concept by which VCs invest in promising companies that have the near-term potential to list their shares on a stock exchange.

Look for the third post in the series next week.

(1)    Burt T. & Hutchinson N. Funding the Development of Antibody Innovations. Part 1: Entrepreneurial Antibody Scientists.

 

Filed Under: Antibody discovery, Finance, Venture capital Tagged With: antibody discovery, antiverse

Funding the Development of Antibody Innovations, Part 1: Entrepreneurial Antibody Scientists

May 19, 2021 by The Antibody Society

By Tom Burt (Partner, Sofinnova Partners) & Nick Hutchinson (BSG Lead, Mammalian Cell Culture, FUJIFILM Diosynth Biotechnologies)

The Antibody Society has partnered with Tom Burt, Partner at Sofinnova Partners, a leading European venture capital firm in life sciences, specializing in healthcare and sustainability to produce a 4-part series of articles explaining the basics of financing a start-up biotech company. Our aim is to support and inspire researchers working in labs with a passion for their science and the drive to push their ideas as far as they will go. In Part 1, we discuss the characteristics of the entrepreneurial antibody scientist.

As of 2021, the pipeline of therapeutic antibodies is strong and the biopharmaceutical industry is enjoying unprecedented success in bringing new products to market (1). The launch of new antibody drugs can have a tremendous impact on the lives of patients suffering from diseases for which there are either no existing treatments or current treatments are lacking. Technological developments, such as Fc engineering, bi- and multi-specific antibody formats and antibody-drug conjugates will lead to improved antibody treatments in the future. Not all advances in antibody science are new drugs, however, and many are leading to new enabling research tools and novel diagnostics. The amount of innovation in the sector, driven by creative scientists working in labs around the world, is startling.

Scientists developing antibody therapeutics must progress the idea through discovery and development phases, including preclinical and clinical testing, with various regulatory hurdles that must be navigated before commercial launch can take place. Large pharma and biotech companies are well versed in managing the complexity and costs of antibody development and commercialization, but there is always room in the market for smaller, more agile players who can compete on an equal footing with these giants.

Entrepreneurial scientists are eschewing the traditional career pathways of staying in academia or joining large pharma companies (2) in favor of establishing their own companies. They are raising money to finance discovery and development, while managing their biotech businesses in order to turn their ideas into a reality. By adopting this approach, founders can retain much greater control of their inventions, can align the development of their technology with their own values, and furthermore, stand to benefit financially if their candidate is shown to be successful.

“It’s an excellent time to be considering raising finance for biotech start-ups. Investors have lots of capital that is waiting to be deployed and society is re-considering how it values medtech innovations in light of the pandemic,” explained Tom.

Investors’ attitudes to these different types of start-up will vary depending on the size of the investment that the company will need, the level of risk associated with the investment, the size of the likely return and the time it will take to see a return. Raising finance for different types of antibody start-up companies will depend on the business model and the nature of the innovation being commercialized. A technology for antibody discovery embedded in a piece of equipment will differ from an amino acid sequence that can be licensed, which will differ from an antibody therapeutic requiring ten years and hundreds of millions if not billions of dollars before any revenues are generated.

“Investors in therapeutics are very wary of “one-trick ponies” with only a single drug candidate,” says Tom. “We look for companies with innovative technologies that might be applied to a number of candidates for multiple disease targets. This reduces risks by ensuring the start-up can have multiple shots on goal.”

One such example is the start-up antibody company Gigagen, which was recently acquired by Grifols, a specialist in plasma-derived medicine. Gigagen’s Magnify Platform enables the identification of rare novel targets within the tumor microenvironment, which in turn can be fed into its Surge Platform, allowing the production of recombinant polyclonal antibodies derived from mammalian repertoires. The company has an oncology pipeline containing monoclonal and bispecific antibodies and a recombinant polyclonal immunoglobulin pipeline, which includes treatments for COVID-19 and other infectious diseases.

Like other start-up biotechs, Gigagen had licensed these platforms technologies to other antibody discovery and development companies in order to generate early revenues, before using them as a springboard to launch their own candidate development programmes.

In the next three posts in this series, we’ll explain the start-up financing cycle and how it relates to antibody companies, especially those developing antibody products for therapeutic use. We’ll use industry examples to describe different types of investors in antibody innovations, what they look for in a company or idea, and their expectations as to how the funding is utilized. We will also explain how the funding cycle is changing, which will help inventors fund the clinical journey more easily.

Watch for our second post next week!

1.       Kaplon H & Reichert JM (2021) Antibodies to watch in 2021. mAbs.

2.       Friedman J. How Biotech Startup Funding Will Changing in the Next 10 Years.

 

Filed Under: Antibody discovery, Finance, Venture capital Tagged With: financing, funding, Gigagen, venture capital

Dostarlimab approved by FDA for endometrial cancer

April 22, 2021 by The Antibody Society

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.

Filed Under: Antibody therapeutic, Food and Drug Administration Tagged With: antibody therapeutics, dostarlimab, Food and Drug Administration

Science Writing Competition

April 21, 2021 by The Antibody Society

Attention Student & Post-doc members:
Our Science Writing Competition is now open!
Submission deadline: July 1, 2021

Clear, concise communication is essential to make your science accessible! The Antibody Society is offering you a chance to grow this skill through a Science Writing Competition.

We invite you to submit an essay of 1200 – 1500 words on a topic related to antibody research. Feel free to use an eye-catching self-generated high-resolution graphic (jpg format) to help make your main point. Relevant topics include, but are not limited to:

  • Antibody engineering
  • Antibody therapeutics
  • Fc effector function and neutralization
  • Bispecific antibodies
  • Antibody-drug conjugates
  • Adaptive immune receptor repertoires

The winning essays will be featured on The Antibody Society’s website, and winners will be offered an opportunity to give a short talk on their essay topic in a Society webcast. Winners will also receive free registration to one meeting we co-promote, as listed on our Upcoming Meetings page, or one of the following meetings that we organize:

  • Emerging Immunotherapeutics for Ovarian Cancer (Sep 2021; details to be announced)
  • Adaptive Immune Receptor Repertoire Community Meeting VI: Exploring New Frontiers (Dec 2021)
  • Antibody Engineering & Therapeutics (Dec 2021)

Two winners (1 student, 1 post-doc) will be selected by our panel of judges based on the originality, creativity, clarity, and structure of their essays.

Submission deadline: July 1, 2021

Winners will be announced by July 9, 2021.

Entry is limited to The Antibody Society student and post-doc members. Submission details and the competition rules are found here.

Not a member? Click here to register for your free membership!

Filed Under: The Antibody Society Tagged With: Science Writing

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

April 15, 2021 by The Antibody Society

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.

Filed Under: Antibody therapeutic Tagged With: antibody therapeutics, EGFR

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