Masked Antibodies & Cytokines As Prodrugs: a landscape analysis of stakeholders, technologies, pipelines, business and financing from an industry perspective

Abstract
Masked Antibodies & Cytokines As Prodrugs:

a landscape analysis of stakeholders, technologies, pipelines, business and financing from an industry perspective

This report provides you with a landscape description and analysis of prodrug antibodies and cytokines employing conventional and novel masking technology platforms from an industry perspective as of October 2021.

The prodrug concept of masking technologies is an elegant approach to address the selectivity limitations of conventional therapeutic antibodies and cytokines.

The report brings you up-to-date with information about and analysis of

Stakeholders in the field: technology and major pharmaceutical companies and investors;
Masking technologies: conventional (kinetically controlled); pH dependent and protease cleavage in the tumor microenvironment
Targets of masked antibodies and type of masked cytokine selected for development of masked biologics;
Business strategy: pure play (foundational or converted) masking technology company, diversified technology company, exit options, preferred antibody modality or type of cytokine, investment case;
Financing situation of technology companies and key investors in the field;
Partnering deals with financial terms;
Major pharmaceutical companies: preferences for masking technologies, collaboration and licensing agreements.
Background

Therapeutic antibodies have become a clinically and commercially successful treatment modality with more than 100 antibodies approved for therapy and commercial sales of more than US$ 184 bln in the year 2020. However, systemic administration of monoclonal antibodies or cytokines may induce severe adverse events with mechanism-of-action effects, meaning off-tumor on-target toxicity in healthy tissue. In order to increase the selectivity of antibodies and cytokines at the disease site, antibodies should ignore the target antigen and cytokines the receptor in normal healthy tissue and be preferentially active in the disease region.

The use of antibody prodrugs is one new strategy for more specific tumor targeting of biological therapies. Conventional prodrugs are pharmacologically inactive compounds that are converted into active forms in the body after administration. They can be designed to be activated at the intended site of action, thereby lowering exposure of normal tissues to active drug and minimizing toxicity. The most common novel approach to creating antibody prodrugs are protease-activated antibodies that use antigen binding site ‘masks’. The mask is typically a recombinant protein extension of the light and/or heavy chain of the antibody that has been designed to block access to the antigen binding site and physically prevent binding of the antibody to the cognate antigen. A protease substrate sequence is also inserted between the mask and the antibody. When the prodrug antibody enters the tumor microenvironment, upregulated proteases that are common in cancer tissues cleave the substrate sequence, the mask separates from the antibody, and the antibody becomes competent to bind to its target in the tumor. This doesn’t happen efficiently in normal tissues because there is insufficient extracellular protease activity to remove the mask. The same principle does apply to prodrug cytokines.

Methodology

This report evaluates the industry landscape of masked antibodies and cytokines in research and development. The report is based on the identification and description of 40 stakeholder, 24 of which are companies with masking technologies and 16 are pharma/biotech companies partnered with masking technology companies.

For each masking technology company, a profile has been elaborated providing information about the company background/history, the financial situation, relevant technology, partnering deals and target & pipeline overview. Short profiles are provided for pharma & biotech companies with a stake in masking technologies. The company profiles are preceded by a chapter of stakeholder analysis.

Profiles of 20 different masking technologies were also elaborated and presented separately for masking technology onloy applied to antibodies, only applied to cytokines and applied to both, antibodies and cytokines. The masking technologies are analyzed with special focus on origin of technology, inactivation domain, linkers and substrates for protease cleavage. Conventional and universal masking technologies are also discussed.

Eventually, profiles of 25 masked antibody R&D programs and of 10 masked cytokine programs. Each masked antibody profile was assigned to one of three groups: immuno-oncology antibodies; antibody-drug conjugates (ADC) and T-cell engaging (TCE) bi- or trispecific antibodies. Masked cytokine profiles are presented separately for interleukin-2 (IL-2); IL-12 & IL-15; and interferon alpha. Discussion of the masked antibody programs includes applied masking technology, targets or type of cytokine, stage of development, preclinical and clinical experience.

In a separate chapter, aspects of business models, financing and partnering are presented and discussed. Further stakeholders of masking technologies include investment firms which are presented by company and investment round. Financial terms of partnering deals are also described and discussed.

All information in the three chapters of Company Profiles, Technology Profiles and Drug Candidate Profiles are fully referenced with 79 scientific references, in many cases with hyperlinks leading to the source of information (abstracts, Posters, papers). Non-scientific references, such as press releases, annual reports or company presentations, are disclosed within the text with an embedded hyperlink leading to the online source of information. Details about R&D strategy, collaboration and licensing agreements, financing rounds & sources are described in the company profiles.

The report further includes 35 tables to summarize and directly compare information and uses illustrations to explain principles of masking technologies.

What will you find in the report?
-Profiles of antibody & cytokine masking technology companies active in the field;
-Description of major pharma’s/biotech’s role in the field (in-house R&D, partnering and investing);
-Comprehensive description and analysis of emerging masked antibodies and cytokines;
-Pharmacologic profiles of selected masked antibodies and cytokines;
-Characterization, profiling and state of antibody & cytokine masking technologies;
-Target selection for each antibody masking technology;
-Selection of type of cytokine for each cytokine masking technology;
-Description and analysis of financing rounds (capital raised, investors);
-Economic terms of collaboration and licensing deals;
-Sources of financing.

Who will benefit from the report?
-Venture capital, private equity and investment managers;
-Managers of Big Pharma venture capital firms;
-Financial analysts;
-Business development and licensing (BDL) specialists;
-CEO, COO and managing directors;
-Corporate strategy analysts and managers;
-Chief Technology Officer;
-R&D Portfolio, Technology and Strategy Management;
-Clinical and preclinical development specialists.

Content
1 Executive Summary
2 Introduction, Overview & Methodology
3 Stakeholder Analysis
3.1 Overview
3.2 Masking Technology Companies
3.3 Pharma/Biotech Companies Partnered with Masking Technology Companies
4 Profiles of Stakeholders in Masking Technologies
4.1 Profiles of Masking Technology Companies
4.1.1 Accurus Bioscience
4.1.2 Adagene
4.1.3 Amunix Pharmaceuticals
4.1.4 Ascendis Pharma
4.1.5 AskGene Pharma
4.1.6 BioAtla
4.1.7 Bright Peak Therapeutics
4.1.8 CytomX Therapeutics
4.1.9 GlycoNEX
4.1.10 Harpoon Therapeutics
4.1.11 Janux Therapeutics
4.1.12 Maverick Therapeutics
4.1.13 Meditope Biosciences
4.1.14 Molecular Partners
4.1.15 Nektar Therapeutics
4.1.16 Revitope Oncology
4.1.17 SeaGen
4.1.18 Shanghai Affinity Biopharmaceutical
4.1.19 Tansoar Biotech
4.1.20 Trutino Biosciences
4.1.21 Werewolf Therapeutics
4.1.22 Xilio Therapeutics
4.1.23 Zymeworks
4.2 Profiles of Pharma & Biotech Companies with a Stake in Masking Technologies
4.2.1 AbbVie
4.2.2 ADC Therapeutics
4.2.3 Amgen
4.2.4 Astellas Pharma
4.2.5 BeiGene
4.2.6 Boehringer Ingelheim
4.2.7 Bristol Myers Squibb
4.2.8 Exelixis
4.2.9 I-Mab Biopharma
4.2.10 Immunogen
4.2.11 Janssen
4.2.12 Junshi Biosciences
4.2.13 Merck
4.2.14 Mitsubishi Tanabe Pharma
4.2.15 Pfizer
4.2.16 Roche
4.2.17 Takeda Pharmaceutical Co
5 Analysis of Masking Technologies
5.1 Origin of Masking Technologies
5.2 Prodrug Antibody Technologies
5.3 Prodrug Cytokine Technologies
5.4 Prodrug Antibody & Cytokine Technologies
6 Profiles of Masking Technologies
6.1 Masking Technologies Appied Only To Antibodies
6.1.1 Adagene: SAFEbody Technology
6.1.2 BioAtla: Conditionally Active Biologics (CAB)
6.1.3 Harpoon Therapeutics: ProTriTAC Technology
6.1.4 Janux Therapeutics: Tumor Activated T Cell Engager (TRACTr) Technology
6.1.5 Maverick Therapeutics: COBRA Technology
6.1.6 Molecular Partners: Anti-CD3 ProDrug DARPin (CD3-PDD) Technology
6.1.7 Revitope Oncology: PrecisionGATE Technology Platform
6.1.8 Roche: Protease-Activated T-Cell Bispecific (TCB) Antibodies
6.1.9 SeaGen: Coiled-Coil Masking Domain Technology
6.1.10 Tansoar Biotech: Universal Antibody Lock Technology
6.2 Masking Technologies Applied Only To Cytokines
6.2.1 Ascendis Pharma: TransCon Technology
6.2.2 AskGene Pharma: Smartkine Prodrug Technology
6.2.3 Meditope Biosciences: SnAP Technology
6.2.4 Nektar Therapeutics: Kinetically Controlled Prodrug Technology
6-2.5 Trutino Biosciences: On-Demand-Cytokine (ODC) Platform
6.2.6 Werewolf Therapeutics: PREDATOR Technology Platform
6.3 Masking Technologies Applied to Antibodies & Cytokines
6.3.1 Amunix Pharmaceuticals: Pro-XTEN Technology
6.3.2 CytomX Therapeutics: Probody Technology
6.3.3 Xilio Therapeutics: Geographically Precise Solutions (GPS) platform
6.3.4
Zymeworks: PROTECT Technology Platform
7 Analysis of Pipeline and Masked Antibody & Cytokine Prodrug Candidates
7.1 Introduction
7.2 Analysis of the Pipeline of Masked Antibodies
7.2.1 Overview of the Masked Antibody Pipeline
7.2.2 Pipeline of EGFR-Targeted Masked Antibodies
7.2.3 Pipeline of CTLA4-Targeted Masked Antibodies
7.2.4 Pipeline of EpCAM-Targeted Masked Antibodies
7.2.5 Pipeline of Her2-Targeted Masked Antibodies
7.2.6 Pipeline of Masked Antibodies Targeting TROP2, PSMA or B7-H3
7.2.7 Pipeline of Other Masked Antibodies with Designated Targets
7.2.8 Clinical Proof of Mechanism and Concept
7.3 Analysis of the Pipeline of Masked Cytokines
7.3.1 Pipeline of Masked Interleukin-2 Molecules
7.3.2 Pipeline of Masked Interleukin-12 and -15 Molecules
7.3.3 Pipeline of Masked Interferon alpha Molecules
8 Profiles of Masked Antibody & Cytokine Product Candidates
8.1 Masked Immuno-Oncology Antibodies
8.1.1 ADG126
8.1.2 Anti-CD47 Prodrug Antibody
8.1.3 BA3071
8.1.4 BMS-986249
8.1.5 BMS-986288
8.1.6 CX-188
8.1.7 Pacmilimab
8.1.8 PD-L1 x CD28 Costimulatory Bispecific
8.1.9 XTX101
8.2 Masked Antibody-Drug Conjugates
8.2.1 CX-2029
8.2.2 CX-2043
8.2.3 Mecbotamab vedotin
8.2.4 Ozuriftamab vedotin
8.2.5 Praluzatamab ravtansine
8.3 Masked T-Cell Engaging (TCE) Antibodies
8.3.1 AMX-818
8.3.2 BA3182
8.3.3 CX-904
8.3.4 EGFR-TRACTr
8.3.5 EGFR-XPAT
8.3.6 Her2-PROTECT-CD3
8.3.7 HPN601
8.3.8 PSMA-TRACTr
8.3.9 TAK-186
8.3.10 TAK-280
8.3.11 TROP2-TRACTr
8.4 Masked Interleukin-2 (IL-2) Cytokines
8.4.1 Bempegaldesleukin
8.4.2 ODC-IL2
8.4.3 TransCon IL-2 β/γ (beta/gamma)
8.4.4 WTX-124
8.4.5 XTX202
8.5 Masked Interleukin-12 (IL-12) and -15 (IL-15) Cytokines
8.5.1 ASKG215β (beta) and ASKG215γ (gamma)
8.5.2 ProTECT IL-12 Fc
8.5.3 WTX-330
8.6 Masked Interferon (IFN) Cytokines
8.6.1 Dual Masked Interferon α2b (alpha2b)
8.6.2 WTX-613
9 Business, Financing & Partnering
9.1 Business
9.2 Financing
9.3 Partnering
10 References

Figures & Tables
Table 1 Corporate Stakeholders in Masking Technologies
Table 2 Focus of Masking Technology Companies
Table 3 Profiles of Companies with Masking Technologies
Table 4 Interests of Pharma/Biotech Companies in Applications of Masking Technologies
Table 5 Partnerships between Masking Technology Companies and Pharma/Biotech Companies
Table 6 Levels of Interest and Participation of Major Pharma/Biotech Companies in Masking Technologies
Table 7 Adagene’s Partnered SAFEbody Discovery Programs
Table 8 Adagene’s SAFEbody Pipeline
Table 9 Amunix Pharmaceuticals’ Unpartnered Pipeline of XPATs and XPACs
Table 10 BioAtla’s Pipeline of Conditionally Active Biologics (CABs)
Table 11 Pipeline of Proprietary and Partnered Probody Therapeutics from CytomX Therapeutics
Table 12 TRACTr & TRACIr Pipeline of Janux Therapeutics
Table 13 Maverick Therapeutics’ Pipeline of COBRA Molecules
Table 14 Werewolf Therapeutics’ Pipeline of Indukine Molecules
Table 15 Xilio Therapeutics’ Pipeline of Masked Antibodies and Cytokines
Table 16 Source of Technology and Pharma Partners of Foundational Masking Technology Companies
Tables 17 Foundational & Main Technology Platforms of Companies with Evolution to Masking Technologies
Table 18 Overview of Applications of Masking Technologies to Different Antibody Constructs
Table 19 Characteristics of the Masking Moiety Used for Generation of Prodrug Antibodies
Table 20 Characteristics of the Linker Moiety Used for Generation of Prodrug Antibodies
Table 21 Overview of Applications of Masking Technologies to Different Cytokines
Table 22 Characteristics of the Masking Moiety Used for Generation of Prodrug Cytokines
Table 23 Characteristics of the Linker Moiety Used for Generation of Prodrug Cytokines
Table 24 Overview of Applications of Masking Technologies to Different Cytokines & Antibody Constructs
Table 25 Characteristics of the Masking Moiety Used for Generation of Prodrug Antibodies & Cytokines
Table 26 Characteristics of the Linker Moiety Used for Generation of Prodrug Antibodies & Cytokines
Table 27 Overview of Masked Antibody R&D Programs
Table 28 Overview of Antibody Modality and R&D Stage of Masked Antibodies
Table 29 Overview of Antibody Modality and Targets of Masked Antibodies
Table 30 EGFR-Targeted Masked Antibody Programs in R&D
Table 31 CTLA4-Targeted Masked Antibody Programs in R&D
Table 32 EpCAM-Targeted Masked Antibody Programs in R&D
Table 33 Her2-Targeted Masked Antibody Programs in R&D
Table 34 Masked Antibody Programs Targeting TROP2, PSMA or B7-H3
Table 35 Pipeline of Other Masked Antibodies with Designated Targets
Table 36 Synopsis of Clinical Results of Masked Antibodies
Table 37 Overview of Masked Cytokine Programs in R&D
Table 38 Overview of Type of Cytokine and R&D Stage for Masked Cytokines
Table 39 Overview of Masked Interleukin-2 Programs in R&D
Table 40 Overview of Masked Interleukin-12 & -15 Programs in R&D
Table 41 Overview of Masked Cytokine Programs in R&D
Table 42 Financing of Converted Pure Play Masking Technology Companies
Table 43 Financing of Foundational Pure Play Masking Technology Companies
Table 44 Financial Terms of Partnering Deals Based on Masking Technology