Japanese drugmaker Eisai & Co and Chinese drug developer Bliss Biopharmaceutical (Hangzhou) Co., have entered into a joint development agreement to further develop BB-1701, an antibody-drug conjugate (ADC). As part of the agreement Eisai & Co obtained option rights for a strategic collaboration.[1]

BB-1701 is an ADC being developed by Bliss Biopharmaceutical and is composed of Eisai’s in-house developed anticancer payload agent eribulin (Halaven®; Eisai & Co), a fully synthetic, structurally simplified, macrocyclic ketone analogue of the marine natural product halichondrin B, produced from the marine sponge Halichondria okadai, conjugated to an anti-HER2 antibody via a REsidue-SPEcific linker. [1]

Eribulin is a a market approved agent for the treatment of metastatic breast cancer and liposarcoma, and considered an effective payload for the development of novel antibody-drug conjugates.

Clinical trials
Preclinical study results, presented at the annual meeting of the American Association for Cancer Research (AACR), held April 14-19, 2023 at the Orange County Convention Center in Orlando, Florida, showed that BB-1701 exhibits potent and specific cytotoxicity activities to various types of cancer cells where HER2-exprssing levels vary in large ranges.[2]

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The study outcomes show that BB-1701 induced tumor-growth suppression, even regression in in vivo models with a single dose of 1-5 mg/kg dosage. In comparison, the investigators reported that other HER2-targeting antibody-drug conjugates with payloads including mertansine (also called DM1, a thiol-containing maytansinoid), monomethyl auristatin E (MMAE), and Dxd (a topoisomerase I inhibitor, exatecan derivative), eribulin-containing antibody-drug conjugates demonstrated higher potency to cancer cell lines with low HER2 expressing levels (with lower IC50).[2]

The investigators also observed that BB-1701 demonstrated effective tumor suppression in models insensitive to trastuzumab emtansine (Kadcyla®l Genentech/Roche) or fam-trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca).[3][4]

In addition mode of action studies revealed significant bystander cytotoxicity of BB-1701 to HER2-low cells when co-cultured with HER2-high cells. Additionally, treatment with BB-1701 increased adenosine triphosphate (ATP) releasing and Calreticulin (calregulin, CRP55, or CaBP3) expression, both deemed immunogenic cell death (ICD) markers.

The investigators further noted that repeat dose pharmacokinetic and toxicology studies in non-human primates revealed favorable pharmacokinetic (PK) and safety profiles of BB-1701 in the clinical intend dosage route and schedule.

These outcomes favor BB-1701 as a potent anti-tumor agent to cancers including HER2-low expressing and/or cancers insensitive to other HER2-targeting ADCs.

Proprietary technology
The linker-payload is a proprietary technology platform developed by Eisai’s U.S. research base Exton Site, and Eisai is investigating the possibilities of using this platform to link to various antibodies.

“BB-1701 is characterized by its payload of eribulin, which is a product of our modern synthetic organic chemistry that has already made contributions to patients with breast cancer and soft tissue sarcoma,” said Takashi Owa, MD, Chief Scientific Officer, Senior Vice President, Eisai Co.

“Our collaboration with BlissBio will accelerate the development of BB-1701 with the goal of bringing a new treatment option to patients globally,” Owa added.

Continued collaboration
Under a license agreement signed by the two companies in 2018, Eisai has granted BlissBio global exclusive development rights for several ADCs to use eribulin as the payload. Based on preclinical data and the status of the Phase 1 / 2 clinical trials of BB-1701 currently being conducted by BlissBio, the both companies have decided to co-develop this drug.

Upfront payments
Under the terms of the joint development agreement, Eisai will make upfront and development milestone payments to BlissBio, conduct a Phase 2 clinical trial in breast cancer, and obtain option rights to develop and commercialize BB-1701 globally, excluding Greater China (China, Hong Kong, Macau, Taiwan).

If Eisai exercises the option rights, an additional upfront payment will be made to BlissBio, as well as development and regulatory milestone payments, sales milestone payments and a certain amount of royalties on sales revenue of BB-1701 after the launch. If all development, regulatory and sales milestones are achieved, Eisai will pay up to a total of US $ 2 billion.

Clinical trials
A First-in-human Study of Multiple Doses of BB-1701 in Subjects With Locally Advanced/Metastatic HER2 Expressing Solid Tumors – NCT04257110

Highlights of prescribing information
Eribulin (Halaven®; Eisai & Co)[Prescribing Information]
Ado-trastuzumab emtansine (Kadcyla®l Genentech/Roche) [Prescribing Information]
Fam-trastuzumab deruxtecan-nxki (Enhertu®; Daiichi Sankyo and AstraZeneca) [Prescribing Information]

[1] ADC Drug map, ADC Review | Journal of Antibody-drug Conjugates. Online. Last accesses on May 8, 2023.
[2] Wang Y, Xia B, Cao L, Yang J, Feng C, Jiang F, Li C, Gu L, Yang Y, Tian J, Cheng C, Furuuchi K, Fulmer J, Verdi A, Rybinski K, Soto A, Albone E, Uenaka T, Gong L, Liu T, Qin Q, Wei Z, Zhou Y. Preclinical development of BB-1701, a HER2-tageting eribulin-containing ADC with potent bystander effect and ICD activity. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1887.
[3] ADC Drug map, ADC Review | Journal of Antibody-drug Conjugates. Online. Last accesses on May 8, 2023.
[4] ADC Drug map, ADC Review | Journal of Antibody-drug Conjugates. Online. Last accesses on May 8, 2023.

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