scholarly journals Trop-2 protein as a therapeutic target: A focused review on Trop-2-based antibody-drug conjugates and their predictive biomarkers

2021 ◽  
Author(s):  
Semir Vranic ◽  
Zoran Gatalica
Keyword(s):  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Antibody Drug Conjugates ◽  
New Class ◽  
Drug Conjugates ◽  
Current Review ◽  
Urothelial Carcinomas ◽  
Solid Malignancies ◽  
Biomarker Analysis ◽  
Antibody Drug

Antibody-drug conjugates (ADCs) represent a new class of highly potent antineoplastic drugs built by attaching a small molecule of an anticancer drug (payload) or another therapeutic agent to an antibody recognizing an epitope on the targeted cells. Trophoblast cell-surface antigen-2 (Trop-2) was originally described in trophoblasts and fetal tissues, but subsequently, its overexpression has been demonstrated in various solid malignancies. Sacituzumab govitecan, a conjugate of anti-Trop-2 antibody and SN-38 payload (an active metabolite of irinotecan), is the first in the class that has been clinically validated and approved by the Food and Drug Administration for the treatment of metastatic triple-negative breast (2020) and urothelial carcinomas (2021). In the current review, we summarize and critically appraise the most recent advances with Sacituzumab govitecan, emphasizing the predictive biomarker analysis.

A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity

2016 ◽  
Vol 15 (8) ◽  
pp. 1870-1878 ◽  
Author(s):  
Michael L. Miller ◽  
Nathan E. Fishkin ◽  
Wei Li ◽  
Kathleen R. Whiteman ◽  
Yelena Kovtun ◽  
...  
Keyword(s):  
Antibody Drug Conjugates ◽  
New Class ◽  
Drug Conjugates ◽  
Alkylating Activity ◽  
Antibody Drug

Abstract 224: Antibody-drug conjugates (ADCs) of a new class of N-10 amino linked DNA alkylating indolino-benzodiazepines (IGNs)

2019 ◽  
Author(s):  
Michael L. Miller ◽  
Emily E. Reid ◽  
Katie E. Archer ◽  
Luke Harris ◽  
Erin K. Maloney ◽  
...  
Keyword(s):  
Antibody Drug Conjugates ◽  
New Class ◽  
Drug Conjugates ◽  
Antibody Drug

scholarly journals Site-Specific Antibody–Drug Conjugates in Triple Variable Domain Fab Format

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 764 ◽  
Author(s):  
Dobeen Hwang ◽  
Christoph Rader
Keyword(s):  
Tumor Tissue ◽  
In Vitro Cytotoxicity ◽  
Variable Domain ◽  
Site Specific ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Solid Malignancies ◽  
Antibody Drug

The interest in replacing the conventional immunoglobulin G (IgG) format of monoclonal antibodies (mAbs) and antibody–drug conjugates (ADCs) with alternative antibody and antibody-like scaffolds reflects a need to expand their therapeutic utility and potency while retaining their exquisite specificity, affinity, and low intrinsic toxicity. For example, in the therapy of solid malignancies, the limited tumor tissue penetration and distribution of ADCs in IgG format mitigates a uniform distribution of the cytotoxic payload. Here, we report triple variable domain Fab (TVD–Fab) as a new format that affords the site-specific and stable generation of monovalent ADCs without the Fc domain and a drug-to-antibody ratio (DAR) of 2. TVD–Fabs harbor three variable fragment (Fv) domains: one for tumor targeting and two for the fast, efficient, precise, and stable conjugation of two cargos via uniquely reactive lysine residues. The biochemical and in vitro cytotoxicity properties of a HER2-targeting TVD–Fab before and after conjugation to a tubulin inhibitor were validated. In vivo, the TVD–Fab antibody carrier revealed a circulatory half-life of 13.3 ± 2.5 h and deeper tumor tissue distribution compared to our previously reported dual variable domain (DVD)–IgG1 format. Taken together, the TVD–Fab format merits further investigations as an antibody carrier of site-specific ADCs targeting solid malignancies.

scholarly journals Perspectives on the development of antibody-drug conjugates targeting ROR1 for hematological and solid cancers

2021 ◽  
Author(s):  
Haiyong Peng
Keyword(s):  
Cancer Therapy ◽  
Small Molecules ◽  
Pharmaceutical Companies ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Solid Malignancies ◽  
Selective Delivery ◽  
And Performance ◽  
Antibody Drug ◽  
Made In

Abstract Antibody–drug conjugates (ADCs) are targeted therapeutics generated by conjugation of cytotoxic small molecules to monoclonal antibodies (mAbs) via chemical linkers. Due to their selective delivery of toxic payloads to antigen-positive cancer cells, ADCs demonstrate wider therapeutic indexes compared to conventional chemotherapy. After decades of intensive research and development, significant advances have been made in the field, leading to a total of ten FDA-approved ADCs to treat cancer patients. Currently, ~ 80 ADCs targeting different antigens are under clinical evaluation for treatment of either hematological or solid malignancies. Notably, 3 ADCs targeting the same oncofetal protein, ROR1, have attracted considerable attention when they were acquired or licensed successively in the fourth quarter of 2020 by 3 major pharmaceutical companies. Apparently, ROR1 has emerged as an attractive target for cancer therapy. Since all the components of ADCs, including the antibody, linker, and payload, as well as the conjugation method, play critical roles in ADC’s efficacy and performance, their choice and combination will determine how far they can be advanced. This review summarizes the design and development of current anti-ROR1 ADCs and highlights an emerging trend to target ROR1 for cancer therapy.

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