A potent anti-CD70 antibody-drug conjugate combining a dimeric pyrrolobenzodiazepine drug with site-specific conjugation technology.

@article{Jeffrey2013APA,
  title={A potent anti-CD70 antibody-drug conjugate combining a dimeric pyrrolobenzodiazepine drug with site-specific conjugation technology.},
  author={Scott C. Jeffrey and Patrick J. Burke and Robert P. Lyon and David W Meyer and Django Sussman and Martha E. Anderson and Joshua H. Hunter and Chris I Leiske and Jamie B. Miyamoto and Nicole D. Nicholas and Nicole M. Okeley and Russell J. Sanderson and Ivan J. Stone and Weiping Zeng and Stephen J Gregson and Luke Masterson and Arnaud C Tiberghien and Philip Howard and David E. Thurston and C L Law and Peter D. Senter},
  journal={Bioconjugate chemistry},
  year={2013},
  volume={24 7},
  pages={
          1256-63
        }
}
A highly cytotoxic DNA cross-linking pyrrolobenzodiazepine (PBD) dimer with a valine-alanine dipeptide linker was conjugated to the anti-CD70 h1F6 mAb either through endogenous interchain cysteines or, site-specifically, through engineered cysteines at position 239 of the heavy chains. The h1F6239C-PBD conjugation strategy proved to be superior to interchain cysteine conjugation, affording an antibody-drug conjugate (ADC) with high uniformity in drug-loading and low levels of aggregation. In… 

Figures and Tables from this paper

ADCT-301, a Pyrrolobenzodiazepine (PBD) Dimer–Containing Antibody–Drug Conjugate (ADC) Targeting CD25-Expressing Hematological Malignancies
TLDR
Dose-dependent increases in DNA cross-linking, γ-H2AX, and PBD payload staining were observed in tumors in vivo indicating a role as relevant pharmacodynamic assays, and support the clinical testing of this novel ADC in patients with CD25-expressing tumors.
Site-Specific Conjugation of Monomethyl Auristatin E to Anti-CD30 Antibodies Improves Their Pharmacokinetics and Therapeutic Index in Rodent Models.
TLDR
The in vitro and in vivo characterization of four novel ADCs that are based on the anti-CD30 antibody cAC10, which has the same polypeptide backbone as ADCETRIS, suggest that homogeneous ADCs display improved pharmacokinetics and better therapeutic indexes compared to those of chemically modified ADCs with variable DARs.
Pyrrolobenzodiazepine Dimer Antibody-Drug Conjugates: Synthesis and Evaluation of Noncleavable Drug-Linkers.
TLDR
Noncleavable PBD-ADCs exhibit potent activity, particularly in HER2 models, and in vivo antitumor efficacy for the anti-HER2 ADCs in Founder 5 was observed with tumor stasis at 0.5-1 mg/kg, 1 mg/ kg, and 3-6mg/kg for 6, 8, and 7, respectively.
Design and characterization of homogenous antibody-drug conjugates with a drug-to-antibody ratio of one prepared using an engineered antibody and a dual-maleimide pyrrolobenzodiazepine dimer
TLDR
Flexmab technologies, in combination with SG3710, provide a platform for generating site-specific homogenous PBD-based ADCs with DAR of one, which have improved biophysical properties and tolerability compared to conventional site- specific PBD/PBD/DAR of two ADCs.
Preclinical Evaluation of MEDI0641, a Pyrrolobenzodiazepine-Conjugated Antibody–Drug Conjugate Targeting 5T4
TLDR
Given that the 5T4-PBD possessed both potent antitumor activity as well as anti-CSC activity, and thus could potentially target bulk tumor cells and CSCs in target-positive indications, it was further evaluated in non-GLP rat toxicology studies that demonstrated excellent in vivo stability with an acceptable safety profile.
Production of site-specific antibody-drug conjugates using optimized non-natural amino acids in a cell-free expression system.
TLDR
A cell-free protein expression system for production of antibody drug conjugates is established through site-specific incorporation of the optimized non-natural amino acid, para-azidomethyl-l-phenylalanine (pAMF), and a novel variant of the Methanococcus jannaschii tyrosyl tRNA synthetase (TyrRS), with a high activity and specificity toward pAMF is discovered.
Design, Synthesis, and Structure-Activity Relationships of Novel Tetrahydroisoquinolino Benzodiazepine Dimer Antitumor Agents and Their Application in Antibody-Drug Conjugates.
TLDR
In vitro, these antibody drug conjugates (ADCs) exhibited significant cytotoxic and target-mediated selectivity on human cancer cell lines, and the pharmacokinetic profiles, high target specificity, and robust antitumor activity were observed in these models after a single dose of the ADC-46.
Antibody-Drug Conjugates Bearing Pyrrolobenzodiazepine or Tubulysin Payloads Are Immunomodulatory and Synergize with Multiple Immunotherapies.
TLDR
It is shown that payloads induced an immune response that prevented the growth of tumors following subsequent tumor cell challenge, and synergy was observed in some cases with suboptimal doses of ADCs, potentially providing an approach to achieve potent antitumor responses while minimizing ADC-induced toxicity.
Modulating Therapeutic Activity and Toxicity of Pyrrolobenzodiazepine Antibody–Drug Conjugates with Self-Immolative Disulfide Linkers
TLDR
Overall, these data suggest that the novel self-immolative disulfide linker represents a valuable way to construct ADCs with equivalent efficacy and improved safety.
...
...

References

SHOWING 1-10 OF 50 REFERENCES
Enhanced activity of monomethylauristatin F through monoclonal antibody delivery: effects of linker technology on efficacy and toxicity.
TLDR
Several new linkers were generated in which various components within the L1 linker were either altered or deleted to optimize the ADC, and one of the most promising linkers contained a noncleavable maleimidocaproyl (L4) spacer between the drug and the mAb.
Development and properties of beta-glucuronide linkers for monoclonal antibody-drug conjugates.
TLDR
Results demonstrate that the beta-glucuronide linker system is an effective strategy for targeting cytotoxic agents providing ADCs with high degrees of efficacy at well-tolerated doses.
Development of potent monoclonal antibody auristatin conjugates for cancer therapy
TLDR
The in vitro and in vivo properties of monoclonal antibody (mAb)-drug conjugates consisting of the potent synthetic dolastatin 10 analogs auristatin E (AE) and monomethylaurists E (MMAE), linked to the chimeric mAbs cBR96 and cAC10, illustrate the importance of linker technology, drug potency and conjugation methodology in developing safe and efficacious mAb-drug conjugs for cancer therapy.
Design, synthesis, and biological evaluation of antibody-drug conjugates comprised of potent camptothecin analogues.
TLDR
ADCs bearing the potent camptothecin analogue, 7-butyl-9-amino-10,11-methylenedioxy-camptothein, were highly potent and immunologically specific on a panel of cancer cell lines in vitro, and efficacious at well-tolerated doses in a renal cell carcinoma xenograft model.
Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index
TLDR
The favorable in vivo properties of the near-homogenous composition of this conjugate suggest that the strategy offers a general approach to retaining the antitumor efficacy of antibody-drug conjugates, while minimizing their systemic toxicity.
Effects of Drug Loading on the Antitumor Activity of a Monoclonal Antibody Drug Conjugate
TLDR
By decreasing drug loading per antibody, the therapeutic index was increased demonstrating that drug loading is a key design parameter for antibody-drug conjugates.
Novel peptide linkers for highly potent antibody-auristatin conjugate.
TLDR
Results demonstrate that manipulation of the C-terminal peptide sequence used to attach auristatins to the mAb carrier can lead to highly potent and specific conjugates with greatly improved therapeutic windows.
Design, synthesis, and in vitro evaluation of dipeptide-based antibody minor groove binder conjugates.
TLDR
In vitro cytotoxicity assays established that the mAb-MGB drug conjugates were highly cytotoxic and effected immunologically specific cell kill at subsaturating doses.
...
...