Advances in Antibody–Drug Conjugate Design: Current Clinical Landscape and Future Innovations

Gauzy-Lazo, Laurence; Sassoon, Ingrid; Brun, Marie-Priscille

doi:10.1177/2472555220912955

Cited by 56 publications

(58 citation statements)

References 193 publications

(271 reference statements)

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“…Antibody-drug conjugates (ADC) represent one promising and popular drug delivery system, which utilizes antibody-specificity to direct small molecules directly to the target of interest. Although only eight ADCs have gained clinical approval so far, at least seventy ADCs are at present in clinical trials [ 61 ]. Anti-cancer therapy delivering cytotoxic molecules is the main focus of current ADCs in clinical trials or on the market but the use of the ADC technology for delivery of immunomodulatory molecules in macrophages in inflammatory diseases is also evolving.…”

Section: Targeting Macrophages In Inflammatory and Malignant Diseamentioning

confidence: 99%

“…So far, only immunoliposomes targeting CD163 have been investigated in animal models of cancers. No immunoliposomes have gained clinical approval [ 310 , 311 ] whereas multiple ADCs have clinical approval though or have entered clinical trials [ 61 ]. In a drug-development perspective, it would therefore be highly relevant also to investigate CD163 targeting ADCs as a drug delivery system in cancer therapy.…”

Section: Targeting Cd163 + Macrophagesmentioning

confidence: 99%

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Targeting of CD163+ Macrophages in Inflammatory and Malignant Diseases

Skytthe

Graversen

Moestrup

2020

IJMS

138

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The macrophage is a key cell in the pro- and anti-inflammatory response including that of the inflammatory microenvironment of malignant tumors. Much current drug development in chronic inflammatory diseases and cancer therefore focuses on the macrophage as a target for immunotherapy. However, this strategy is complicated by the pleiotropic phenotype of the macrophage that is highly responsive to its microenvironment. The plasticity leads to numerous types of macrophages with rather different and, to some extent, opposing functionalities, as evident by the existence of macrophages with either stimulating or down-regulating effect on inflammation and tumor growth. The phenotypes are characterized by different surface markers and the present review describes recent progress in drug-targeting of the surface marker CD163 expressed in a subpopulation of macrophages. CD163 is an abundant endocytic receptor for multiple ligands, quantitatively important being the haptoglobin-hemoglobin complex. The microenvironment of inflammation and tumorigenesis is particular rich in CD163+ macrophages. The use of antibodies for directing anti-inflammatory (e.g., glucocorticoids) or tumoricidal (e.g., doxorubicin) drugs to CD163+ macrophages in animal models of inflammation and cancer has demonstrated a high efficacy of the conjugate drugs. This macrophage-targeting approach has a low toxicity profile that may highly improve the therapeutic window of many current drugs and drug candidates.

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Section: Targeting Macrophages In Inflammatory and Malignant Diseamentioning

confidence: 99%

Section: Targeting Cd163 + Macrophagesmentioning

confidence: 99%

Targeting of CD163+ Macrophages in Inflammatory and Malignant Diseases

Skytthe

Graversen

Moestrup

2020

IJMS

138

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“…These strategies include insertion of engineered cysteine residues, insertion of unnatural amino acids in the antibody sequence or enzymatic conjugation through glycotransferases and transglutaminases [ 66 , 69 , 70 , 71 ]. Some ADCs with site-specific conjugation in phase I clinical trials are MEDI2228, PF-06804103 and TR1801-ADC ( Table 3 ) [ 72 ].…”

Section: Design and Structure Of Antibody–drug Conjugatesmentioning

confidence: 99%

Antibody–Drug Conjugates for Cancer Therapy

et al. 2020

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Antibody–drug conjugates (ADCs) are novel drugs that exploit the specificity of a monoclonal antibody (mAb) to reach target antigens expressed on cancer cells for the delivery of a potent cytotoxic payload. ADCs provide a unique opportunity to deliver drugs to tumor cells while minimizing toxicity to normal tissue, achieving wider therapeutic windows and enhanced pharmacokinetic/pharmacodynamic properties. To date, nine ADCs have been approved by the FDA and more than 80 ADCs are under clinical development worldwide. In this paper, we provide an overview of the biology and chemistry of each component of ADC design. We briefly discuss the clinical experience with approved ADCs and the various pathways involved in ADC resistance. We conclude with perspectives about the future development of the next generations of ADCs, including the role of molecular imaging in drug development.

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“…So far, several antigens have been reported overexpressed in cancer tissues that can be exploited as targets for ADCs [ 10 ]. The antigen must be recognized and bound by the antibody with a reasonable affinty (Kd ≤ 10 nM) to ensure rapid uptake in the target cell [ 11 ].…”

Section: Basic Characteristics Of the Conjugatementioning

confidence: 99%

“…The approved ADCs are mostly indicated for the treatment of hematological malignancies and, with a few exceptions, their clinical activity has largely failed for solid tumors. The reasons for these failures may be attributed to the large molecular size of the ADC molecule that shows poor penetration into the tumor mass, thus resulting in poor in vivo efficacy [ 11 ]. For this reason, other forms of reduced sized antibodies such as single chain fragments of variable regions (scFv), i.e., v regions joined by a linker peptide, have been investigated, Also in the form of heterodimers of IgG and IgE, a small divalent immunoprotein (SIP, 75 kDa) or “minibody”, a homodimer stabilized by a disulfide bond to its C-terminal [ 13 ].…”

Section: Future Perspectivesmentioning

confidence: 99%

Antibody-Drug Conjugates: The New Frontier of Chemotherapy

Ponziani

Vittorio²,

Pitari

et al. 2020

IJMS

106

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In recent years, antibody-drug conjugates (ADCs) have become promising antitumor agents to be used as one of the tools in personalized cancer medicine. ADCs are comprised of a drug with cytotoxic activity cross-linked to a monoclonal antibody, targeting antigens expressed at higher levels on tumor cells than on normal cells. By providing a selective targeting mechanism for cytotoxic drugs, ADCs improve the therapeutic index in clinical practice. In this review, the chemistry of ADC linker conjugation together with strategies adopted to improve antibody tolerability (by reducing antigenicity) are examined, with particular attention to ADCs approved by the regulatory agencies (the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA)) for treating cancer patients. Recent developments in engineering Immunoglobulin (Ig) genes and antibody humanization have greatly reduced some of the problems of the first generation of ADCs, beset by problems, such as random coupling of the payload and immunogenicity of the antibody. ADC development and clinical use is a fast, evolving area, and will likely prove an important modality for the treatment of cancer in the near future.

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Advances in Antibody–Drug Conjugate Design: Current Clinical Landscape and Future Innovations

Cited by 56 publications

References 193 publications

Targeting of CD163+ Macrophages in Inflammatory and Malignant Diseases

Targeting of CD163+ Macrophages in Inflammatory and Malignant Diseases

Antibody–Drug Conjugates for Cancer Therapy

Antibody-Drug Conjugates: The New Frontier of Chemotherapy

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