Exelixis and Swedish BioInvent International have entered into an option and license agreement focused on the identification and development of novel antibodies for use in IO therapeutics. The collaboration is intended to expand Exelixis’ portfolio of antibody-based therapies and will combine BioInvent’s cancer immunology and antibody biology expertise with Exelixis’ expertise and resources in antibody engineering and antibody-drug conjugate (ADC) technologies, and proven history of developing and commercializing oncology therapeutics.

BioInvents is a clinical-stage biotech company that discovers and develops novel and first-in-class immuno-modulatory antibodies for cancer therapy as has currently three drug candidates in four ongoing clinical programs in Phase 1/2 trials for the treatment of hematological cancer and solid tumors, respectively and a fifth program just initiating clinical development. To support the company’s research and development, BioInvents generates revenues from research collaborations and license agreements with multiple top-tier pharmaceutical companies, as well as from producing antibodies for third parties in the company’s fully integrated manufacturing unit.

BioInvent has several licensing agreements and research collaborations with leading pharmaceutical companies (including Pfizer, Merck & Co/MSD, Bayer, Daiichi Sankyo, and others, including an exclusive licensing agreement with CASI Pharmaceuticals for BI-1206 in mainland China, Taiwan, Hong Kong and Macau and a co-developing agreement to develop oncolytic virus candidates for solid tumors, leveraging BioInvent’s n-CoDeR® and F.I.R.S.T™ platforms.

Oncology focused
Exelixis is an oncology-focused biotechnology company focusing on accelerating the discovery, development and commercialization of new anti-cancer agents for difficult-to-treat cancers. The company’s discovery efforts has resulted in four commercially available products, cabozantinib (Cabometyx®/Cometriq®), cobimetinib (Cotellic®) and esaxerenone (Minnebro®). [1]

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In addition, Excelixis has entered into partnerships with leading pharmaceutical, biotech and drug Development companies, including French biotech company Ipsen, Genentech/Roche, Takeda and Daiichi Sankyo, to bring novel therapies to patients worldwide. [1]

Catalent’s SMARTag® platform 
In 2020 Catalent and Exelixis partnered to develop novel antibody-drug conjugates using Catalent’s SMARTag® bioconjugation platform and monoclonal antibodies from Exelixis’ growing preclinical pipeline. Developed by Catalent’s Redwood Bioscience subsidiary, the SMARTag® technology platform provides optimized site-specific protein-modification and linker technologies for ADCs and other bioconjugates.[2]

The SMARTag platform technology overcomes the limitations associated with traditional protein chemistries that produce heterogeneous products with variable conjugate potency, toxicity, and stability and enables the development of ADCs with a wider therapeutic window and improved manufacturability. Investigational ADCs based on the SMARTag technology have demonstrated promising results in the clinic, highlighting the potential to create ADCs with significantly expanded therapeutic indices.

That same year, Exelixis also signed an agreement with NBE-Therapeutics to discover and develop multiple antibody-drug conjugates for oncology applications by leveraging NBE’s unique expertise and proprietary platforms in ADC discovery, including site-specific conjugation and novel payloads.

Using NBE-Therapeutic’s technology platforms, including Transpo-mAb Display for antibody discovery and SMAC-Technology for site-specific conjugation and ADC manufacture, the companies agreed to improves upon older ADC technology platforms by delivering highly homogenous, stable and potent ADCs with immune-stimulatory function and potential for improved therapeutic index in multiple cancer indications. In addition, NBE-Therapeutics developed a proprietary PNU-anthracycline based, DNA-targeting toxin platform that yields highly potent and immune-stimulatory ADCs (iADCs).

Exelixis’ Pipeline

Exelixis has an extensive pipeline which includes a number of investigational (ADC) drug candidates, including XB002 (formerly known as ICON-2; Iconic Therapeutics),  a next-generation ADC composed of a human monoclonal antibody against tissue factor (TF) that is conjugated to a cytotoxic agent. This rationally designed next-generation ADC leverages Zymeworks’ proprietary ZymeLink™ linker-payload, that includes a suite of proprietary cytotoxins, stable linkers, and conjugation technologies compatible with traditional antibodies, proteins, and is designed to overcome the limitations of existing ADCs.

The available preclinical data shows that XB002, in contrast with prior therapies in this class, binds to tissue factor without affecting the blood coagulation cascade. The data also demonstrated encouraging activity of XB002 in multiple solid tumor models and improved tolerability compared with other tissue factor-targeting ADCs. XB002 has shown significant tumor growth inhibition and, in some cases, complete regression.

Exelixis has acquired broad rights to use the anti-tissue factor antibody incorporated into XB002, for any application, including conjugated to other payloads, as well as rights within oncology to a number of other anti-tissue factor antibodies developed by Iconic, including for use in ADCs and multi-specific biologics. This approach fits Exelixis’ intention to expand the development of XB002, both as a monotherapy and in combination with other therapies, into indications other than those currently addressed by commercially available TF-targeting therapies. An ongoing phase 1 clinical study (Jewel-101/NCT04925284) is designed to evaluate XB002 as a monotherapy in multiple solid tumor indications.

XB010 is the first custom ADC generated through Exelixis collaboration network, which was designated a development candidate in late 2021 and will enter preclinical development in 2022. In designing XB010, Exelixis sourced antibodies from Invenra and worked with its partners at Catalent to design a novel ADC with broad potential.

“As Exelixis seeks to build a differentiated next-generation pipeline in oncology, we’re leveraging Invenra’s expertise in antibody and bispecific discovery to provide key building blocks for potential future Exelixis biologics, including antibody-drug conjugates,” noted Peter Lamb, Ph.D., Executive Vice President, Scientific Strategy and Chief Scientific Officer of Exelixis.

XB010 targets the oncofetal antigen 5T4 which is overexpressed on a broad array of solid tumors, including non-small cell cancer (NSCLC), head and neck squamous cell carcinomas (HNSCC), and gastric and breast carcinomas, and utilizes Catalent’s SMARTag site specific conjugation platform to produce a homogeneous ADC with a defined drug-antibody ratio. XB010 also incorporates Catalent’s next-generation linker technology which required two cleavage events to release the monomethyl auristatin E (MMEA) payload and is designed to be significantly more stable than first-generation approaches. The investigational agent is well tolerated in vivo with potential for a good therapeutic index. [3]

Exelixis’ plans to advance up to five new development candidates into preclinical development during 2022, including XB010 and additional ADC programs, as well as small molecule programs that include a mixture of both next-generation approaches to established targets and opportunities to be first-in-class treatments.

BioInvent Partnership
Based on the new agreement, Exelixis and BioInvent will collaborate on target and antibody discovery using BioInvent’s proprietary n-CoDeR® antibody library and patient-centric F.I.R.S.T™ screening platform, which together allow for parallel target and antibody discovery.

BioInvents antibody library n-CoDeR® contains more than 30 billion human antibody genes stored within phages in test tubes. These act as production units for various antibodies, making it possible to search the library to identify precisely those antibodies that bind to a specific target protein.

This library is searched using an established technology called phage display. To identify an optimal antibody, BioInvent has developed automated processes in which robots carry out the analysis on an industrial scale.

Martin Welschof is Chief Executive Officer of BioInvent.

F.I.R.S.T™ screening platform
The F.I.R.S.T™ screening platform is BioInvents’ screening tool which is used for the company’s internal drug development as well as for external development partners. The platform is patient-centred and facilitates the development of new antibody therapies, as new drug candidates can be produced without detailed knowledge of the antibodies’ target proteins. This unique method has the advantage of simultaneously identifying disease-associated targets and antibodies that bind to them.

BioInvents’ F.I.R.S.T™ screening technology makes it possible to simultaneously investigate antibody binding to both diseased and healthy tissue in order to select those antibodies and targets that are unique to diseased tissue in terms of binding and expression. Through functional, high-capacity screening, antibodies are then selected on the basis of, for example, their ability to induce cell death of primary cancer cells or improve the immune system’s capacity to eliminate tumor cells.

Terms of the Agreement
Under the terms of the agreement, Exelixis will pay BioInvent an upfront fee of US $ 25 million in exchange for rights to select three targets identified using BioInvent’s proprietary F.I.R.S.T platform and n-CoDeR library. BioInvent will be responsible for initial target and antibody discovery activities, and characterization of antibody mechanism of action.

Peter Lamb, Ph.D. is Exelixs’ Executive Vice President, Scientific Strategy and Chief Scientific Officer

Exelixis will have the right to exercise an option to in-license any of the target programs upon identification of a development candidate directed to that target. Upon option exercise, Exelixis will pay BioInvent an option exercise fee and will assume responsibility for all future development and commercialization activities for the development candidate, including potential ADC and bispecific antibody engineering activities. In addition, BioInvent will be eligible for success-based development and commercialization milestones, as well as tiered royalties on the annual net sales of any products that are successfully commercialized under the collaboration.

“Expanding our biotherapeutics pipeline is a key strategic priority, and this agreement provides Exelixis with access to BioInvent’s antibody and cancer immunology expertise centered around the innovative F.I.R.S.T discovery platform, which rapidly screens samples from patients with cancer to identify antibodies and targets with promising therapeutic potential,” said Exelixis’ Peter Lamb.

“We believe this patient-centric and biology-driven approach has great potential to identify novel targets and enable the development of differentiated antibody-based IO therapies,” Lamb added.

“BioInvent is committed to translating our expertise in cancer immunology and antibody mechanism of action into innovative IO therapies that can improve outcomes for patients,” said Martin Welschof, Chief Executive Officer of BioInvent.

“Exelixis has a demonstrated track record of success in both commercializing important new oncology medicines and establishing highly productive collaborations that integrate diverse and complementary skill sets and technologies – such as toxin and cytokine conjugation of monoclonal antibodies for ADC and bispecific monoclonal antibody technologies – to enable the identification and development of innovative therapies with significant clinical and commercial potential,” Welschof noted.

“We believe that our cancer immunology expertise and discovery platform will support Exelixis’ mission to expand its biologic pipeline, and we very much look forward to working together,” he concluded.

Clinical trials
Study of XB002 in Subjects With Solid Tumors (JEWEL-101) – NCT04925284

Highlights of prescribing information
Cabozantinib (Cabometyx®; Exelixis/Ipsen)[Prescription information]

[1] Garcia, D. Encouraging Results for Cabozantinib Mono- and Combination Therapy Across Different Tumor Types. Onco’Zine. June 6, 2022 [Article]
[2] Drake P. SMARTag® ADC Stands Out in the Crowd of HER2-targeted Conjugates – ADC Review | Journal of Antibody-drug Conjugates, September 29, 2020 [Article]
[2] Corporate presentation during the 40th annual JP Morgen virtual Healthcare Conference, held January 10 – 13, 2022

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