Antibody–drug conjugates: What drives their progress?

Pander, Giulia; Uhl, Philipp; Kühl, Nikos; Haberkorn, Uwe; Anderl, Jan; Mier, Walter

doi:10.1016/j.drudis.2022.06.011

Cited by 10 publications

(8 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While MMAE is too toxic to be administered as a free drug in humans, it is already employed for cancer treatment in the course of targeted therapies using ADCs. 1,2 Additionally, several ADCs carrying MMAE are under evaluation in the clinic for the therapy of solid tumors, including CRC. 44 Since our study suggests that Bev potentiates the anticancer activity of MMAE, it could be of interest to investigate the effects of Bev on the therapeutic efficacy of ADCs transporting this antimitotic agent.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Combination of Targeted Therapies for Colorectal Cancer Treatment

Péraudeau,

Renoux,

Emambux

et al. 2023

Mol. Pharmaceutics

View full text Add to dashboard Cite

The design of innovative therapeutic strategies enabling the selective destruction of tumor cells while sparing healthy tissues remains highly challenging in cancer therapy. Here, we show that the combination of two targeted therapies, including bevacizumab (Bev), and a β-glucuronidase-responsive albumin-binding prodrug of monomethyl auristatin E (MMAE), is efficient for the treatment of colorectal cancer implanted in mice. This combined therapy produces a therapeutic activity superior to that of the association of FOLFOX and Bev currently used to treat patients with this pathology. The increased anticancer efficacy is due to either a synergistic or an additive effect between Bev and MMAE selectively released from the glucuronide prodrug in the tumor microenvironment. Since numerous drug delivery systems such as antibody−drug conjugates employ MMAE as a cytotoxic payload, this finding may be of great interest for improving their therapeutic index by combining them with Bev, particularly for the therapy of colorectal cancer.

show abstract

Section: ■ Results and Discussionmentioning

confidence: 99%

Combination of Targeted Therapies for Colorectal Cancer Treatment

Péraudeau,

Renoux,

Emambux

et al. 2023

Mol. Pharmaceutics

View full text Add to dashboard Cite

show abstract

“…Despite the large number of clinical assets, detailed analysis of the ADC landscape reveals surprisingly little variation in design: (a) the monoclonal antibody is always IgG (typically IgG1), (b) the linker release mechanism is almost exclusively based on protease-sensitive dipeptides or redox-sensitive disulfides, and (c) payload mode of action in the vast majority of cases is limited to tubulin inhibition, DNA damaging agents, or topoisomerase 1 inhibition. One important ADC parameter is the drug-to-antibody ratio (DAR), which typically varies between 2 and 8 depending on payload cytotoxicity; the least potent payloads such as topoisomerase 1 inhibitors (SN-38, DXd) are typically applied at a high drug loading (DAR7–8), and ADCs with payloads of high potency (tubulin inhibitors like MMAE and maytansinoids) are typically used to generate average DAR4, while ultrapotent molecules (e.g., calicheamicin, PBD dimer, PNU-159,682, and amanitin) are predominantly conjugated at low stoichiometry (average DAR2) . Despite the low payload loading of the latter ADC category, it must be noted that the clinically administered dose is typically (substantially) below 1 mg/kg; for example, Mylotarg and Besponsa are dosed at <200 μg/kg, Zynlonta is dosed at 150 μg/kg, and loncastuximab-tesirine is dosed as low as 45 μg/kg.…”

Section: Introductionmentioning

confidence: 99%

Generation of DAR1 Antibody-Drug Conjugates for Ultrapotent Payloads Using Tailored GlycoConnect Technology

Bever¹,

Popal²,

Schaik³

et al. 2023

Bioconjugate Chem.

View full text Add to dashboard Cite

GlycoConnect technology can be readily adapted to provide different drug-to-antibody ratios (DARs) and is currently also evaluated in various clinical programs, including ADCT-601 (DAR2), MRG004a (DAR4), and XMT-1660 (DAR6). While antibody-drug conjugates (ADCs) typically feature a DAR2–8, it has become clear that ADCs with ultrapotent payloads (e.g., PBD dimers and calicheamicin) can only be administered to patients at low doses (<0.5 mg/kg), which may compromise effective biodistribution and may be insufficient to reach target receptor saturation in the tumor. Here, we show that GlycoConnect technology can be readily extended to DAR1 ADCs without the need of antibody re-engineering. We demonstrate that various ultrapotent, cytotoxic payloads are amenable to this methodology. In a follow-up experiment, HCC-1954 tumor spheroids were treated with either an AlexaFluor647-labeled DAR1 or DAR2 PBD-based ADC to study the effect on tumor penetration. Significant improvement of tumor spheroid penetration was observed for the DAR1 ADC compared to the DAR2 ADC at an equal payload dose, underlining the potential of a lower DAR for ADCs bearing ultrapotent payloads.

show abstract

“…5−9 However, in recent years, technological advancements facilitating site-specific conjugation with engineered or natural amino acids have led to continuous increases in homogeneity and optimal DAR. 8,9 Specific examples include the approval of Adcetris was developed by the introduction of cysteine-engineered residues into the antibody via site-directed mutagenesis providing free thiol groups for conjugation with thiol-specific maleimide linkers. This technology generates almost homogeneous ADCs containing approximately 2 DAR, but additional antibody reduction/oxidation steps are required for the selective conjugation of the added cysteines.…”

Section: Introductionmentioning

confidence: 99%

“…Both factors are technologically challenging and require efficient methods for producing completely homogeneous ADCs . Due to the challenges with producing homogeneous ADCs, previous food and drug administration (FDA) approved ADCs were developed and administered as heterogeneous mixtures due to the conventional and nonselective bioconjugation strategies used in their production resulting in a wide range of DARs. − However, in recent years, technological advancements facilitating site-specific conjugation with engineered or natural amino acids have led to continuous increases in homogeneity and optimal DAR. , Specific examples include the approval of Adcetris (brentuximab vedotin) by the FDA in 2011. Adcetris was developed by the introduction of cysteine-engineered residues into the antibody via site-directed mutagenesis providing free thiol groups for conjugation with thiol-specific maleimide linkers.…”

Section: Introductionmentioning

confidence: 99%

The Chemistry of Creating Chemically Programmed Antibodies (cPAbs): Site-Specific Bioconjugation of Small Molecules

et al. 2023

View full text Add to dashboard Cite

Small-molecule drugs have been employed for years as therapeutics in the pharmaceutical industry. However, small-molecule drugs typically have short in vivo half-lives which is one of the largest impediments to the success of many potentially valuable pharmacologically active small molecules. The undesirable pharmacokinetics and pharmacology associated with some small molecules have led to the development of a new class of bioconjugates known as chemically programmed antibodies (cPAbs). cPAbs are bioconjugates in which antibodies are used to augment small molecules with effector functions and prolonged pharmacokinetic profiles, where the pharmacophore of the small molecule is harnessed for target binding and therefore biological targeting. Many different small molecules can be conjugated to large proteins such as full monoclonal antibodies (IgG), fragment crystallizable regions (Fc), or fragment antigen binding regions (Fab). In order to successfully and site-specifically conjugate small molecules to any class of antibodies (IgG, Fc, or Fab), the molecules must be derivatized with a functional group for ease of conjugation without altering the pharmacology of the small molecules. In this Review, we summarize the different synthetic or biological methods that have been employed to produce cPAbs. These unique chemistries have potential to be applied to other fields of antibody modification such as antibody drug conjugates, radioimmunoconjugates, and fluorophore-tagged antibodies.

show abstract

Antibody–drug conjugates: What drives their progress?

Cited by 10 publications

References 70 publications

Combination of Targeted Therapies for Colorectal Cancer Treatment

Combination of Targeted Therapies for Colorectal Cancer Treatment

Generation of DAR1 Antibody-Drug Conjugates for Ultrapotent Payloads Using Tailored GlycoConnect Technology

The Chemistry of Creating Chemically Programmed Antibodies (cPAbs): Site-Specific Bioconjugation of Small Molecules

Contact Info

Product

Resources

About