Author: Nakamura, Koji ; Pissarra, Pedro D. ; Tsukumo, Yukihito ; Richard, Ana R. ; Yamamoto, Kotaro ; Mertens, Nico ; Takizawa, Fumitake ; Cunnah, Philip J.

Abstract5T4 oncofetal tumor-associated antigen (also known as TPGB or WAIF1) is over-expressed in a wide range of solid tumors but shows very limited expression in normal adult tissues thus suggesting 5T4 as an attractive target for antibody therapy. CBA-1535, originally developed by Biotecnol (UK), is a novel trivalent biological construct named a Tribody™ with two binding sites to the tumor associated antigen 5T4 and one to the T cell expressed antigen CD3ε. CD-3 based T cell engagers (TCE) is one of the attractive strategy to treat cancer patients resistant to conventional therapies, however, the effects of TCE on solid tumors are limited due to the immunosuppressive tumor microenvironment. To overcome this limitation, CBA-1535 is designed to have stronger binding activity to 5T4 with two binding sites, and to have the lower affinity to CD3 than to 5T4 to prevent non-specific T cell activation.CBA-1535 does not have a Fc region with a molecular weight of ~100 kDa and it has a low nM Kd for bivalent binding to 5T4, a 20 to 30 nM Kd for monovalent binding to CD3ε. CBA-1535 efficiently induced T cell activation in human PBMCs as exemplified as CD25 and CD69 expressions and showed cytokine release, i.e., IL-2, IL-6, TNFα, and IFN-ɤ, at the concentration between 0.01 and 10 nM only when co-cultured with target cancer cells, however, those T cell activation and cytokine release were not observed under the conditions without target cancer cells, even at the concentration of 1 µM. In the presence of activated human PBMCs as effector cells, CB-1535 elicited 5T4 expressing target cell cytotoxicity with an EC50 of approximately 1-30 pM in a variety of cancer cells. The anti-tumor efficacy of CB-1535 has examined in immunocompromised mice bearing human lung mesothelioma (MSTO-211H) and alveolar epithelial adenocarcinoma (A549) xenografts (such as the 5T4 expressing target cell) and human PBMCs (as effector cells). Anti-tumor efficacy was observed with complete suppression of tumor growth at doses as low as 1 mg/kg in both xenograft models. No abnormalities related to CBA-1535 administration were observed regarding to body weight and clinical signs. Importantly, CBA-1535 showed a synergistic cytotoxicity against 5T4 expressing target cancer cells in vitro when combined with PD-1 antibody Pembrolizumab in a co-culture experiment. In conclusion, we demonstrated encouraging preclinical profile of CBA-1535 as a novel CD-3 based T-cell engager antibody. These results provide the strong rationale for further clinical evaluation ofCBA-1535 in 5T4 positive tumors. CBA-1535 is now under the phase 1 trial in Japan (jRCT2031210708), with 2 parts, the monotherapy and the combination with Pembrolizumab.Citation Format: Fumitake Takizawa, Kotaro Yamamoto, Koji Nakamura, Ana R. Richard, Philip J. Cunnah, Nico Mertens, Pedro D. Pissarra, Yukihito Tsukumo. Preclinical characterization of CBA-1535, a novel bi-specific tribody, with two binding sites to 5T4 and one site to CD3ε [abstract]. 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 2937.

01 Jan 2019·Journal of ImmunotherapyQ4 · MEDICINE

T-cell Activating Tribodies as a Novel Approach for Efficient Killing of ErbB2-positive Cancer Cells

Q4 · MEDICINE

Article

Author: Riccio, Gennaro ; Rubino, Valentina ; De Lorenzo, Claudia ; Saraiva, Kathy ; Passariello, Margherita ; Ricardo, Ana Rita ; Cunnah, Philip ; Mertens, Nico

The Tyrosine Kinase Receptor ErbB2 (HER2) when overexpressed in breast cancer (BC) is associated with poor prognosis. The monoclonal antibody Trastuzumab has become a standard treatment of ErbB2+BC. The antibody treatment has limited efficacy, often meets resistance and induces cardiotoxicity. T-cell recruiting bispecific antibody derivatives (TRBA) offer a more effective alternative to standard antibody therapy. We evaluated a panel of TRBAs targeting 3 different epitopes on the ErbB2 receptor either in a bivalent targeting tribody structure or as a monovalent scFv-fusion (BiTE format) for binding, cytotoxicity on Trastuzumab-resistant cell lines, and induction of cardiotoxicity. All three TRBAs bind with high affinity to the ErbB2 extracellular domain and a large panel of ErbB2-positive tumor cells. Tribodies had an increased in vitro cytotoxic potency as compared to BiTEs. It is interesting to note that, Tribodies targeting the epitopes on ErbB2 receptor domains I and II bind and activate lysis of mammary and gastric tumor cells more efficiently than a Tribody targeting the Trastuzumab epitope on domain IV. The first 2 are also active on Trastuzumab-resistant cancer cells lacking or masking the epitope recognized by Trastuzumab. None of the Tribodies studied showed significant toxicity on human cardiomyocytes. Altogether these results make these novel anti-ErbB2 bispecific Tribodies candidates for therapeutic development for treating ErbB2-positive Trastuzumab-resistant cancer patients.

01 May 2017·Journal of ImmunotherapyQ4 · MEDICINE

Superior Suppression of ErbB2-positive Tumor Cells by a Novel Human Triparatopic Tribody

Q4 · MEDICINE

Article

Author: Riccio, Gennaro ; Mertens, Nico ; Passariello, Margherita ; Cunnah, Philip ; Da Fonseca-Ricardo, Ana R. ; De Lorenzo, Claudia

Downregulation of the epidermal growth factor receptor family of receptors is improved by combining different antibodies to noncompetitive epitopes. For ErbB2/HER2 this has already been translated into clinical practice by using a combination of trastuzumab and pertuzumab. Moreover, cocktails of 2 or 3 anti-epidermal growth factor receptor antibodies show an enhanced downregulation of the receptor due to the induction of matrix formation. A more efficient method for inducing matrix formation and receptor downregulation might include the use of trispecific reagents. A triparatopic Tribody consisting of 3 noncompeting ErbB2 binders was compared with equivalent trivalent monoparatopic counterparts, as well as to a cocktail of 3 monoclonal antibodies for its effects on downregulation of the ErbB2 receptor’s kinase activity and survival of several ErbB2-expressing cancer cell lines. The triparatopic Tribody was significantly more efficient in downregulating ErbB2 and inhibiting tumor cell growth than either the control monoparatope tribodies or the combinatorial treatment with the 3 different parental antibodies on all the tested tumor cells, including trastuzumab-resistant cell lines. The enhancement of effectivity was dependent on all 3 binding moieties. Because the novel Tribody allows reduction of the costs of production (as only 1 construct provides the antitumor effects of 3 antibodies) and has an intermediate molecular size (∼100 kDa) well suited for both tumor penetration and acceptable half-life, it has the potential to become a precious tool for therapeutic use particularly in trastuzumab-resistant cancer patients.

News (Medical) associated with Biotecnol Ltd.

05 Sep 2023

·www.biospace.com

Didier Landais is appointed 4P-Pharma's CEO to lead the company into a new chapter of its development

LILLE, France--(BUSINESS WIRE)-- 4P-Pharma, a pioneering biotechnology company based in Lille and specializing in drug regeneration, is thrilled to achieve a significant milestone in its history. During the latest strategic board meeting, the appointment of Didier Landais as the new CEO of 4P-Pharma was confirmed. This press release features multimedia. View the full release here: DIDIER LANDAIS CEO - 4P-PHARMA Founded in 2014 by Revital Rattenbach, 4P-Pharma is entering a new era of its development. On September 1st, 2023, Didier Landais succeeds Revital Rattenbach as CEO of 4P-Pharma. She now holds the position of Executive Chairwoman. With over 30 years of international experience in the pharma/biotech industry, Didier Landais stands out as an executive leader. His career has been marked by accomplishments in key areas such as research and development, strategy, and business development. His extensive international experience and proven leadership position Didier Landais as the ideal choice for this strategic function. His past achievements attest to his exceptional ability to guide our teams towards excellence, turning ambitious visions into tangible results. Together, the new executive will combine forces to expedite the company's development." "We stand on the brink of a pivotal period for 4P-Pharma. The appointment of Didier reinforces our commitment to innovation and growth. His passion for scientific research, coupled with his profound market understanding, will propel forward our mission to transform how we approach health and well-being, driving dynamics of success." stated Revital Rattenbach, 4P-Pharma’s Executive Chairwoman A strong expertise both in France and internationally, to accelerate the development of 4P-Pharma. Didier Landais holds a Ph.D. in Molecular and Cellular Biology from the University Louis Pasteur (Strasbourg), as well as an Executive MBA from ESSEC (Paris). He started his career as a researcher and oncology project leader at the Gene Therapy Division of RPR-Gencell (Sanofi) before assuming the role of Director of Business Development and General Manager of Cell Therapy, overseeing the international development of a cancer vaccine at IDM Pharma. He has also held positions including Director of Development at Biotecnol and Chief Business Officer at Genome Profiling. Under his leadership as Global Head of Licensing, Servier concluded several notable agreements, including with Celsius, Oncodesign, and Seal Rock. More recently, he served as COO and CBO at Labgenius Ltd in London." "Joining 4P-Pharma is a significant step for me. We are developing high-potential molecules that truly transform patients' lives. With the support of Revital and our dedicated teams, I am confident that we will reach new horizons and push the boundaries of innovation even further." expressed Didier Landais, 4P-Pharma’s CEO. As CEO, Didier Landais holds the responsibility for the company's overall strategy in terms of science, partnerships, and external growth. Revital Rattenbach, now 4P-Pharma’s Executive Chairwoman, remains actively involved in financial consolidation and strategic directions, ensuring the continuity of the company's founding vision. 4P-Pharma remains deeply committed to its partners, investors, and its mission to provide innovative solutions to global health challenges." ABOUT 4P-PHARMA 4P-Pharma is a clinical stage biotech company, pioneering in drug regeneration, founded in Lille in 2014. We focus on untreated serious diseases with high unmet medical needs, aiming to rapidly deliver effective, regenerated, first-in-class therapies. The company has developed a proprietary development engine to address the main pain points of traditional drug development: time, costs, and predictability to deliver optimized risk adjusted returns. We leverage assets with a short time to market, strong IP position, and regulatory opportunities (emergency use or conditional marketing authorizations) in blue-ocean markets. Website: LinkedIn: Twitter: The only version of the 4P-Pharma press release that is legally binding is the one in its original language. Translations must always be compared to the source text, which will establish precedence. The press release text resulting from a translation should not be considered official in any way. View source version on businesswire.com: Contacts Press Najette Chaib – nchaib@beyondcom.fr 06 18 38 11 14 Source: 4P-Pharma Smart Multimedia Gallery Photo DIDIER LANDAIS CEO - 4P-PHARMA Logo View this news release and multimedia online at:

Executive ChangeVaccine

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Drug(Targets)	Indications	Global Highest Phase

Cardiotrophin-1(Biotecnol Ltd.)	Myocardial Reperfusion Injury More	Phase 2
ThioBridge Tribody Drug Conjugates(Biotecnol/ PolyTherics)	Neoplasms More	Preclinical
Interferon alpha 5(Biotecnol Ltd.) ( IFNAR )	Infectious Diseases More	Discontinued
5T4-X-CD3 ( 5T4 x CD3 )	Neoplasms More	Pending
CSPG4-X-CD3 ( CD3 x Chondroitin sulfate proteoglycans )	Neoplasms More	Pending

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