Seagen and Sanofi today confirmed that the companies have agreed to fund and commercialize the development of 3 antibody-drug conjugates (ADCs) for up to three cancer targets.

Antibody-drug Conjugates or ADCs are highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with highly potent anti-cancer agents linked via a chemical linker.

Sanofi and ADCs
Nearly a decade ago Sanofi started a collaboration with Immunogen. This collaboration resulted in the ongoing developed tusamitamab ravtansine (SAR408701, a humanized monoclonal antibody that binds carcinoembryonic antigen-related cell adhesion molecule-5 (CEACAM5*) and a cytotoxic maytansinoid that selectively targets CEACAM5-expressing tumor cells with an average Drug-antibody Ratio (DAR) of 3.8). The drug is in phase 3 development for the treatment of patients diagnosed with non-small cell lung cancer (NSCLC). The investigational agent is a potential first-in-class antibody–drug conjugate selectively targets tumor cells expressing CEACAM5 and, in earlier phase 1 studies, demonstrated a favorable safety profile with infrequent hematological toxicities vs that reported for docetaxel. [1][2][3]

In addition the companies initially co-developed SAR566658, an ADC targeting CA6 in for the treatment of patients diagnosed with triple negative breast cancer (TNBC). Although the drug was initially selected further clinical development, as reported at 2016 annual meeting for the American Society of Clinical Oncology (ASCO), and provided a favorable safety profile and encouraging anti-tumor activity (NCT01156870), the development of this ADC was discontinued following the results of phase 2 clinical trials in late stage, metastatic breast cancer. (NCT02984683) (EudraCT2016-001962-27). [4]

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Another project, the development of SAR428926, an anti-LAMP1 ADC being studied for the treatment of solid tumors, was halted following results from a first-in-human phase 1 dose escalation study in patients with advanced solid tumors (NCT02575781).  The drug was later removed from Sanofi’s development pipeline.

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The collaboration with Immunogen also resulted in the development of isatuximab (SAR650984; Sarclisa®; Sanofi Genzyme), an unconjugated anti-CD38 antibody, a drug that is approved in combination with pomalidomide and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor and in combination with carfilzomib and dexamethasone, for the treatment of adult patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy.

Seagen’s partnerships
Seagen, on its own and in collaboration with partners, developed 3 commercially available ADCs, including brentuximab vedotin (Adcetrics®), which is designed to target cells expressing CD30, a key biomarker in peripheral T-cell lymphomas and classical Hodgkin lymphoma; enfortumab vedotin (Padcev®; in collaboration with Astellas), a Nectin-4-directed antibody and microtubule inhibitor conjugate indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer; and tisotumab vedotin (Tivdak®; in collaboration with Genmab), a tissue factor (TF-) directed ADC for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

Seagen and Sanofi collaboration
The announced collaboration between Seagen and Sanofi is expected to result in 3 new ADCs which will use Sanofi’s proprietary monoclonal antibody (mAb) technology and Seagen’s proprietary ADC technology.

“We are excited to be working with Sanofi, a global biopharmaceutical leader, to identify new ways to potentially address unmet medical needs of cancer patients,” said Clay Siegall, Ph.D., President and Chief Executive Officer, Seagen.

“Jointly developing novel ADCs by combining antibodies from Sanofi with Seagen’s proprietary ADC technology, aligns with our strategic priorities to expand the global potential of our pipeline with new first- or best-in-class programs,” Siegall added.

A synergistic combination
“This collaboration will enable the synergistic combination of molecules and platforms to produce candidate medicines with the potential of bringing renewed hope to cancer patients and their families,” noted John Reed, M.D., Ph.D., Global Head of Research and Development, Sanofi.

Under the terms of the collaboration, Seagen and Sanofi will co-fund global development activities and share equally in any future profits. In addition, Sanofi will make an undisclosed payment to Seagen for each of the three targets as they are selected. The first target under the collaboration has already been designated.

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Note
*CEACAM5, is highly expressed on the surface of lung, colorectal, gastric, breast, and other tumor cells, it is, however, weakly expressed in healthy tissues, this makes  it a very compelling target to evaluate new approaches designed to destroy cancer cells but leaving normal, healthy ones, intact.[5]

Clinica trials
Tusamitamab Ravtansine in Patients With CEACAM5-positive Advanced Solid Tumors (CARMEN-BT01) – NCT04659603
Tusamitamab Ravtansine (SAR408701) in Combination With Ramucirumab in Pretreated Participants With Gastric Cancer (CARMEN-GC01) – NCT05071053
Tusamitamab Ravtansine (SAR408701) in Combination With Pembrolizumab and Tusamitamab Ravtansine (SAR408701) in Combination With Pembrolizumab and Platinum-based Chemotherapy With or Without Pemetrexed in Patients With NSQ NSCLC (CARMEN-LC05) (CARMEN-LC05) – NCT04524689
SAR408701 Versus Docetaxel in Previously Treated, Carcinoembryonic Antigen-related Cell Adhesion Molecule 5 (CEACAM5) Positive Metastatic Non-squamous Non-small Cell Lung Cancer Patients (CARMEN-LC03) – NCT04154956
Tusamitamab Ravtansine in NSQ NSCLC Participants With Negative or Moderate CEACAM5 Expression Tumors and High Circulating CEA (CARMEN-LC06) – NCT05245071
Evaluation of SAR408701 in Japanese Patients With Advanced Malignant Solid Tumors – NCT03324113
First in Man Study of SAR566658 Administered in Patients With CA6-Positive and Refractory Solid Tumor – NCT01156870
Study Evaluating Efficacy and Safety of SAR566658 Treatment in Patients With CA6 Positive Metastatic Triple Negative Breast Cancer – NCT02984683
A Study of SAR428926 in Patients With Advanced Solid Tumors – NCT02575781

Highlights of prescribing information
Brentuximab vedotin (Adcetrics®; Seagen)(Prescribing information)
Enfortumab vedotin (Padcev®; Seagen in collaboration with Astellas) (Prescribing information)
Tisotumab vedotin (Tivdak®; Seagen in collaboration with Genmab) (Prescribing Information)

Reference
[1] Gazzah A, Bedard PL, Hierro C, Kang YK, Abdul Razak A, Ryu MH, Demers B, Fagniez N, Henry C, Hospitel M, Soria JC, Tabernero J. Safety, pharmacokinetics, and antitumor activity of the anti-CEACAM5-DM4 antibody-drug conjugate tusamitamab ravtansine (SAR408701) in patients with advanced solid tumors: first-in-human dose-escalation study. Ann Oncol. 2022 Jan 10:S0923-7534(22)00003-5. doi: 10.1016/j.annonc.2021.12.012. Epub ahead of print. PMID: 35026412.
[2] Pouzin C, Tod M, Chadjaa M, Fagniez N, Nguyen L. Covariate analysis of tusamitamab ravtansine, a DM4 anti-CEACAM5 antibody-drug conjugate, based on first-in-human study. CPT Pharmacometrics Syst Pharmacol. 2022 Feb 22. doi: 10.1002/psp4.12769. Epub ahead of print. PMID: 35191618.
[3]Pouzin C, Gibiansky L, Fagniez N, Chadjaa M, Tod M, Nguyen L. Integrated multiple analytes and semi-mechanistic population pharmacokinetic model of tusamitamab ravtansine, a DM4 anti-CEACAM5 antibody-drug conjugate. J Pharmacokinet Pharmacodyn. 2022 Feb 15. doi: 10.1007/s10928-021-09799-0. Epub ahead of print. PMID: 35166967.
[4] Gomez-Roca CA, Boni V, Moreno V, Morris JC, Delord JP, Calvo E, Papadopoulos KP, Rixe O, Cohen P, Tellier A, Ziti-Ljajic S, Tolcher AW. A phase I study of SAR566658, an anti CA6-antibody drug conjugate (ADC), in patients (Pts) with CA6-positive advanced solid tumors (STs)(NCT01156870). Journal of Clinical Oncology, 2016, 34, 15_suppl, 2511-2511
[5] Hammarstrom et al, 2002, in “Tumor markers, Physiology, Pathobiology, Technology and Clinical Applications” Eds. Diamandis E. P. et al., AACC Press, Washington pp 375

An earlier version of this article was published in ADC Review | Journal of Antibody-drug Conjugates on Thursday, March 17, 2022. [Article]

Featured Image: ASCO 2019 Sanofi Booth Courtesy: © 2019 – 2022. Sunvalley Communication. Used with permission.

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