降解抗体偶联物 (DAC) 的全球市场：从产业角度对利害关係人、技术、管道和联盟进行状况分析 (2024)

本报告根据截至2024年9月的行业情况，对DAC（降解抗体偶联物）利益相关者、平台技术、开发/探索管道以及合作项目进行了解释和分析。新药DAC融合了现有技术：抗体药物偶联物（ADC）和靶向蛋白水解剂，旨在结合两种技术的优势并规避其限制。 DAC 将抗体的特异性与难以药物化的标靶蛋白质降解剂的效率结合起来。 DAC 为 ADC 公司提供了使用新型有效负载来提高疗效和治疗窗口的机会，也为靶向蛋白降解 (TPD) 公司提供了改善细胞特异性、半衰期和药物样特性的机会。

DAC 疗法的两个主要用途是：

• 细胞内标靶蛋白降解
• 细胞外标靶蛋白降解

本报告提供以下方面的最新资讯和分析：

• 该产业的利害关係人基于製药公司和 TPD 技术公司的 DAC 活动的公司概况；
• 使用 PROTAC/分子黏合剂进行蛋白?体降解的 DAC 技术，用于细胞内 TPD；
• 易受细胞内降解的蛋白质；
• 用于细胞内降解的E3连接?；
• DAC 技术使用广泛作用的降解剂来处理细胞外 TPD；以及
• 使用溶小体途径降解剂的DAC技术；
• DAC 临床和非临床开发管线；
• DAC临床阶段概况；
• DAC 的药物发现管道；
• DAC 结合技术和结构概念的临床前证明；
• 合作伙伴活动（收购、授权、联合研究）

DAC最初的概念将其定义为化学偶联的肿瘤靶向抗体和PROTAC（蛋白水解靶向嵌合体）。 PROTAC 是大型异双功能小分子，其中一部分透过连接子结合细胞内标靶蛋白(PoI)，例如布鲁顿酪胺酸激?(BTK)，第二部分将PoI 与泛素结合，它与将蛋白质转化为E3 连接?结合，导致细胞质内的蛋白?体降解。儘管大多数 DAC 发现计划都依赖此概念，但使用分子黏合剂代替 PROTAC 的 DAC 也正在接受研究，甚至是第一个进入临床评估的 DAC。分子黏合剂型小分子可作为黏合剂，增强 E3 连接?与 PoI 的相互作用，导致泛素化和蛋白?体降解。 PROTAC 比黏合剂更容易设计，因为 E3 连接?和 PoI 的结合位点是独立的。然而，PROTACs一般分子较大，开发难度较高。另一方面，黏合剂通常具有较小的分子并且更类似于药物。 DAC 的范围目前正在扩展到细胞外空间，用于降解膜结合蛋白和可溶性蛋白。细胞外标靶蛋白降解涉及双特异性生物製剂或小分子，它们将膜结合或分泌的（可溶性）PoI 招募到降解机器中。降解透过跨膜 E3 连接?和细胞激素受体发生，或透过膜结合再循环受体将 PoI 转运至溶小体。

目录

第1章 摘要整理

第2章 简介

第3章 DAC的研究开发的相关利益者的分析

• 製药公司
• 科技企业

第4章 DAC技术的分析

• DAC（降解抗体偶联物）技术概述
• 使用分子黏合型分解器的DAC
• 使用PROTAC型分解器的DAC
• 具有多种效果的 DAC
• 含有溶小体途径降解剂的 DAC

第5章 DAC的研究开发的分析

• DAC临床·非临床开发平台
  • ORM-6151简介
  • ORM-5029简介
• 药物研发阶段的DAC计划的开发平台(管线)
• DAC技术·结构的前临床概念的确证

第6章 DAC领域的联盟的分析

• 企业收购
• 授权合约
• 药物研发合作

第7章 进行DAC的研究开发的企业概要

• 製药企业
  • Bristol Myers Squibb
  • CSPC Pharmaceutical Group
  • Debiopharm
  • Eisai
  • GlaxoSmithKline
  • Merck KGaA
  • Merck & Co. (MSD)
  • Novartis
  • Pfizer
  • Pierre Fabre
  • Roche
  • Vertex Pharmaceuticals
• 科技企业
  • C4 Therapeutics
  • Crossfire Oncology
  • Cullgen
  • EpiBiologics
  • Firefly Bio
  • InduPro
  • Lycia Therapeutics
  • NanoMedSyn
  • NIBEC
  • Nurix Therapeutics
  • Orum Therapeutics
  • Prelude Therapeutics
  • Ubix Therapeutics
  • VectorY Therapeutics

第8章 DAC技术的简介

• AMFA
• CELMoD ADC
• Degraducer
• DELigase
• EpiTAC
• EPriL
• LYTAC & GELYTAC
• PROTAB
• PROxAb
• REULR
• TORPEDO
• TPD2
• uSMITE
• VecTron

第9章 参考文献

This report provides you with a landscape description and analysis of degrader-antibody conjugate (DAC) stakeholders, platform technologies, development and discovery pipelines and partnering deals from an industry perspective as of September 2024. The emerging novel drug modality of degrader-antibody conjugates represents the convergence of the existing technologies of antibody-drug conjugation and targeted protein degradation with the goal of combining the strengths and avoiding the limitations of both technologies. DACs combine the specificity of antibodies with the efficiency of degraders of difficult to drug protein targets. Degrader-antibody conjugates provide plenty of opportunities for ADC companies to use a novel payload to improve efficacy and the therapeutic window and for targeted protein degradation (TPD) companies to improve cell-specificity, half-life and drug-like properties.

The two main uses for Degrader-Antibody Conjugate therapy are:

• Intracellular Targeted Protein Degradation
• Extracellular Targeted Protein Degradation

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

• Stakeholders in the field, by company profiles of DAC activities at pharmaceutical and TPD technology companies;
• DAC technologies using PROTAC and molecular glue for proteasomal degradation for intracellular TPD;
• Proteins-of-interest for intracellular degradation;
• E3 ligases used for intracellular degradation;
• DAC technologies using broadly acting degraders for extracellular TPD; and
• DAC technologies with lysosomal pathway degraders;
• Clinical and non-clinical development pipeline of DACs;
• Profiles of clinical stage DACs;
• DAC discovery pipeline;
• Preclinical proof-of-concept of DAC conjugate technologies and constructs;
• Partnering activities (acquisition, licensing, collaborations)

The original concept of degrader-antibody conjugates defines DACs as tumor-targeted antibodies chemically conjugated to proteolysis-targeting chimera (PROTACs). PROTACs are large heterobifunctional small molecules with one part binding to the intracellular protein of interest (PoI), e.g. Brutons Tyrosine Kinase (BTK), via a linker to a second part which binds to an E3 ligase that ubiquitylates the PoI, resulting in proteasomal degradation in the cytosol. The majority of DAC discovery programs rely on this concept, but DAC using a molecular glue instead of a PROTAC are also being pursued and even are the first in clinical evaluation. Molecular glue-type small molecules act as an glue that enhances the interaction between an E3 ligase and a PoI, leading to its ubiquitylation and proteasomal degradation. PROTACs are easier to design than glues given their independent binding sites to the E3 ligase and the PoI. However, they are generally large molecules that can be challenging to develop, whereas glues are typically smaller and more drug-like. The scope of degrader-antibody conjugates is currently being expanded into the extracellular space for degradation of membrane bound and soluble proteins. Extracellular targeted protein degradation involves bispecific biologics or small molecules that recruit the PoI, either membrane-bound or secreted (soluble), to a degradation machinery. Degradation may occur through a transmembrane E3 ligase, or a cytokine receptor or via a membrane bound recycling receptor for transport of the PoI to the lysosome, which is the typical pathway for the degradation of extracellular proteins.

Methodology:

This report evaluates the industry landscape of degrader-antibody conjugation in research and development. The report provides a comprehensive overview of the R&D and partnering activities of pharmaceutical and technology companies in the field of degrader-antibody conjugates. This report is based on the identification and description of 26 corporate stakeholders: 12 pharmaceutical companies and 14 technology companies. All publicly available information is fully referenced, either with scientific references (abstracts, posters, presentations, full paper) or hyperlinks leading to the source of information, such as press releases, corporate presentations, annual reports, SEC disclosures and homepage content.

The report has four analytical chapters about stakeholders, DAC technologies, DAC R&D including pipeline, and DAC partnering. Analysis is based on information presented in the two subsequent chapters with specific profiles of companies and technologies. A list of scientific references is provided in the last chapter of the report followed by an overview of the Tables in the text.

Table of Contents

1 Executive Summary

2 Introduction

3 Analysis of Stakeholders in Degrader-Antibody Conjugate R&D

• 3.1 Pharmaceutical Companies
• 3.2 Technology Companies

4 Analysis of Degrader-Antibody Conjugate Technologies

• 4.1 Overview of Degrader-Antibody Conjugate Technologies
• 4.2 Degrader-Antibody Conjugates with Molecular Glue-type Degraders
• 4.3 Degrader-Antibody Conjugates with PROTAC-type Degraders
• 4.4 Degrader-Antibody Conjugates with Broadly Acting Degraders
• 4.5 Degrader-Antibody Conjugates with Lysosomal Pathway Degraders

5 Analysis of Degrader-Antibody Conjugate Research & Development

• 5.1 Clinical & Nonclinical Development Pipeline of Degrader-Antibody Conjugates
  • 5.1.1 Profile of ORM-6151
  • 5.1.2 Profile of ORM-5029
• 5.2 Pipeline of Discovery Stage Degrader-Antibody Conjugate Programs
• 5.3 Preclinical Proof-of-Concept of Degrader-Antibody Conjugate Technologies and Constructs

6 Analysis of Partnering in the Field of Degrader-Antibody Conjugate Partnering

• 6.1 Acquisition
• 6.2 Licensing
• 6.3 Discovery Collaborations

7 Profiles of Companies with Degrader-Antibody Conjugate R&D

• 7.1 Pharmaceutical Companies
  • 7.1.1 Bristol Myers Squibb
  • 7.1.2 CSPC Pharmaceutical Group
  • 7.1.3 Debiopharm
  • 7.1.4 Eisai
  • 7.1.5 GlaxoSmithKline
  • 7.1.6 Merck KGaA
  • 7.1.7 Merck & Co. (MSD)
  • 7.1.8 Novartis
  • 7.1.9 Pfizer
  • 7.1.10 Pierre Fabre
  • 7.1.11 Roche
  • 7.1.12 Vertex Pharmaceuticals
• 7.2 Technology Companies
  • 7.2.1 C4 Therapeutics
  • 7.2.2 Crossfire Oncology
  • 7.2.3 Cullgen
  • 7.2.4 EpiBiologics
  • 7.2.5 Firefly Bio
  • 7.2.6 InduPro
  • 7.2.7 Lycia Therapeutics
  • 7.2.8 NanoMedSyn
  • 7.2.9 NIBEC
  • 7.2.10 Nurix Therapeutics
  • 7.2.11 Orum Therapeutics
  • 7.2.12 Prelude Therapeutics
  • 7.2.13 Ubix Therapeutics
  • 7.2.14 VectorY Therapeutics

8 Profiles of Degrader-Antibody Conjugate Technologies

• 8.1 AMFA
• 8.2 CELMoD ADC
• 8.3 Degraducer
• 8.4 DELigase
• 8.5 EpiTAC
• 8.6 EPriL
• 8.7 LYTAC & GELYTAC
• 8.8 PROTAB
• 8.9 PROxAb
• 8.10 REULR
• 8.11 TORPEDO
• 8.12 TPD2
• 8.13 uSMITE
• 8.14 VecTron

9 References