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Adair J.R.,Ithaka Life science Ltd | Howard P.W.,Spirogen Ltd. | Hartley J.A.,University College London | Williams D.G.,University College London | Chester K.A.,University College London
Expert Opinion on Biological Therapy | Year: 2012

Introduction: There is a great unmet need for effective new treatments in cancer, which continues to be a major cause of death. Antibodydrug conjugates (ADCs) are emerging, after a long gestation, as a class of biopharmaceuticals with the potential to address this need by directing highly potent cytotoxic drugs to their point of action. There is increasing interest in ADCs by major pharmaceutical companies and a growing pipeline of candidates for clinical use. This review summarises progress with development of this new class of drugs. Areas covered: The authors describe separately the antibody and drug elements of ADCs and then examine the technology and consequences of linkage. The work is presented in the light of recent developments in the design, using clinical examples where possible. Expert opinion: Since their emergence as independent drugs, antibodies and chemotherapy are being brought together in effective synergy. The conjunction is timely: many of the technical challenges in preparing antibodies have been addressed; potent new drugs are available and linker technology is advancing apace. ADCs however are not just a sum of their individual parts. The current challenge is in understanding the holistic nature of this exciting class of drugs that promise a new avenue for cancer treatment. Target selection, the interaction of ADC with tumour and off-tumour targets and the internalisation of ADCs, are critical to the effective maturation of ADC technology. Ongoing recent developments in attachment sites and linker chemistry can provide fine-tuning of drug loading, elements of ADC PK and off-target ADC toxicity. © 2012 Informa UK, Ltd.

Antonow D.,University of London | Thurston D.E.,University of London | Thurston D.E.,Spirogen Ltd.
Chemical Reviews | Year: 2011

Pyrrolobenzodiazepines (PBD) are an important class of sequence-selective DNA-interactive agents that bind covalently to guanine bases within the minor groove of DNA. The PBD monomers are remarkable in possessing a 3-dimensional shape that allows them to fit perfectly within the minor groove of DNA, partly due to the longitudinal twist created by the chiral center at their C11a-position. A PBD produced synthetically, semisynthetically, or isolated from natural sources can exist as a mixture of two or even three forms or can exist predominantly as just one. Various biochemical and structural studies on PBD-DNA adducts have suggested that the molecules locate themselves with their N10-position pointing toward the floor of the minor groove. A further important feature of the PBDs is that they interact selectively with specific DNA sequences. A significant effort has also been made to increase the base-pair span and sequence-selectivity of PBD molecules so that they might be used as gene-targeting agents in biological experiments and possibly as therapeutic agents.

Rahman K.M.,Kings College London | Jackson P.J.M.,Kings College London | James C.H.,University College London | Basu B.P.,University College London | And 9 more authors.
Journal of Medicinal Chemistry | Year: 2013

DNA binding 4-(1-methyl-1H-pyrrol-3-yl)benzenamine (MPB) building blocks have been developed that span two DNA base pairs with a strong preference for GC-rich DNA. They have been conjugated to a pyrrolo[2,1-c][1,4]benzodiazepine (PBD) molecule to produce C8-linked PBD-MPB hybrids that can stabilize GC-rich DNA by up to 13-fold compared to AT-rich DNA. Some have subpicomolar IC 50 values in human tumor cell lines and in primary chronic lymphocytic leukemia cells, while being up to 6 orders less cytotoxic in the non-tumor cell line WI38, suggesting that key DNA sequences may be relevant targets in these ultrasensitive cancer cell lines. One conjugate, 7h (KMR-28-39), which has femtomolar activity in the breast cancer cell line MDA-MB-231, has significant dose-dependent antitumor activity in MDA-MB-231 (breast) and MIA PaCa-2 (pancreatic) human tumor xenograft mouse models with insignificant toxicity at therapeutic doses. Preliminary studies suggest that 7h may sterically inhibit interaction of the transcription factor NF-κB with its cognate DNA binding sequence. © 2013 American Chemical Society.

SPIROGEN Ltd | Date: 2011-03-07

Compounds of formula (I): Z-CO-A-BNH-Z (I) wherein: Z is H or an amino protecting group; Z is OH, a protected or activated hydroxyl group or Cl; A is an optionally substituted C

Jeffrey S.C.,Seattle Genetics | Burke P.J.,Seattle Genetics | Lyon R.P.,Seattle Genetics | Meyer D.W.,Seattle Genetics | And 17 more authors.
Bioconjugate Chemistry | Year: 2013

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 h1F6 239C-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 vitro cytotoxicity experiments demonstrated that the h1F6239C-PBD was potent and immunologically specific on CD70-positive renal cell carcinoma (RCC) and non-Hodgkin lymphoma (NHL) cell lines. The conjugate was resistant to drug loss in plasma and in circulation, and had a pharmacokinetic profile closely matching that of the parental h1F6239C antibody capped with N-ethylmaleimide (NEM). Evaluation in CD70-positive RCC and NHL mouse xenograft models showed pronounced antitumor activities at single or weekly doses as low as 0.1 mg/kg of ADC. The ADC was tolerated at 2.5 mg/kg. These results demonstrate that PBDs can be effectively used for antibody-targeted therapy. © 2013 American Chemical Society.

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