Typical Antibody–Drug Conjugates

Published on Nov 3, 2016
· DOI :10.1002/9781119060727.CH1
John M. Lambert52
Estimated H-index: 52
(ImmunoGen, Inc.)
Sources
Abstract
📖 Papers frequently viewed together
20162.21Cornea
5 Authors (Mayuko Tsuda, ..., Masakazu Yamada)
11 Citations
201626.60Cancer Cell
20 Authors (John Li, ..., Steven Coats)
144 Citations
24 Citations
References71
Newest
#1Tim JonesH-Index: 8
Last. Matthew BakerH-Index: 18
view all 34 authors...
An important step in drug development is the assignment of an International Nonproprietary Name (INN) by the World Health Organization (WHO) that provides healthcare professionals with a unique and universally available designated name to identify each pharmaceutical substance. Monoclonal antibody INNs comprise a –mab suffix preceded by a substem indicating the antibody type, e.g., chimeric (-xi-), humanized (-zu-), or human (-u-). The WHO publishes INN definitions that specify how new monoclona...
41 CitationsSource
#1Marc Damelin (Pfizer)H-Index: 9
Last. Scott J. DyllaH-Index: 16
view all 28 authors...
Purpose: Triple-negative breast cancer (TNBC) and ovarian cancer each comprise heterogeneous tumors, for which current therapies have little clinical benefit. Novel therapies that target and eradicate tumor-initiating cells (TIC) are needed to significantly improve survival. Experimental Design: A panel of well-annotated patient-derived xenografts (PDX) was established, and surface markers that enriched for TIC in specific tumor subtypes were empirically determined. The TICs were queried for ove...
43 CitationsSource
The high-grade pulmonary neuroendocrine tumors, small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), remain among the most deadly malignancies. Therapies that effectively target and kill tumor-initiating cells (TICs) in these cancers should translate to improved patient survival. Patient-derived xenograft (PDX) tumors serve as excellent models to study tumor biology and characterize TICs. Increased expression of delta-like 3 (DLL3) was discovered in SCLC and LCNEC PDX t...
281 CitationsSource
The antibody–drug conjugate (ADC), IMMU-130, of the moderately cytotoxic topoisomerase I inhibitor, SN-38, and the CEACAM5-targeted humanized antibody (mAb), labetuzumab, was evaluated in model systems of human colon carcinoma and in phase I clinical trials of heavily pretreated patients with metastatic colorectal cancer. The conjugate, designed with a near-homogeneous drug substitution of 7–8 SN-38/mAb and with a linker that released 50% of the drug in ∼20 h, showed significant antitumor effect...
48 CitationsSource
#1Trevor J. HallamH-Index: 10
#2Erik D. Wold (Scripps Research Institute)H-Index: 7
Last. Vaughn V. Smider (Scripps Research Institute)H-Index: 27
view all 4 authors...
Antibody conjugates are important in many areas of medicine and biological research, and antibody–drug conjugates (ADCs) are becoming an important next generation class of therapeutics for cancer treatment. Early conjugation technologies relied upon random conjugation to multiple amino acid side chains, resulting in heterogeneous mixtures of labeled antibody. Recent studies, however, strongly support the notion that site-specific conjugation produces a homogeneous population of antibody conjugat...
51 CitationsSource
#1Kathleen N. Moore (University of Oklahoma Health Sciences Center)H-Index: 44
#2Lainie P. Martin (Fox Chase Cancer Center)H-Index: 28
Last. Michael J. Birrer (Harvard University)H-Index: 109
view all 14 authors...
5518 Background: IMGN853 (mirvetuximab soravtansine) is a FRα-targeting ADC that comprises a FRα-binding antibody conjugated with the potent maytansinoid, DM4. Methods: This phase I trial evaluates the safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of IMGN853 in pts with FRα-positive solid tumors. A recommended phase II dose (RP2D) of 6.0 mg/kg, administered once every three weeks using adjusted ideal body weight was established in the dose-finding phase. Preliminary evidence...
9 CitationsSource
#1E. Erica Hong (ImmunoGen, Inc.)H-Index: 3
#2Hans K. Erickson (ImmunoGen, Inc.)H-Index: 17
Last. John M. Lambert (ImmunoGen, Inc.)H-Index: 52
view all 8 authors...
Coltuximab ravtansine (SAR3419) is an antibody–drug conjugate (ADC) targeting CD19 created by conjugating a derivative of the potent microtubule-acting cytotoxic agent, maytansine, to a version of the anti-CD19 antibody, anti-B4, that was humanized as an IgG1 by variable domain resurfacing. Four different linker-maytansinoid constructs were synthesized (average ∼3.5 maytansinoids/antibody for each) to evaluate the impact of linker-payload design on the activity of the maytansinoid-ADCs targeting...
29 CitationsSource
#1Olga Ab (ImmunoGen, Inc.)H-Index: 10
#2Kathleen R. Whiteman (ImmunoGen, Inc.)H-Index: 13
Last. John M. Lambert (ImmunoGen, Inc.)H-Index: 52
view all 13 authors...
A majority of ovarian and non–small cell lung adenocarcinoma cancers overexpress folate receptor α (FRα). Here, we report the development of an anti-FRα antibody–drug conjugate (ADC), consisting of a FRα-binding antibody attached to a highly potent maytansinoid that induces cell-cycle arrest and cell death by targeting microtubules. From screening a large panel of anti-FRα monoclonal antibodies, we selected the humanized antibody M9346A as the best antibody for targeted delivery of a maytansinoi...
79 CitationsSource
Fully human antibodies from transgenic animals account for an increasing number of new therapeutics. After immunization, diverse human monoclonal antibodies of high affinity can be obtained from transgenic rodents, while large animals, such as transchromosomic cattle, have produced respectable amounts of specific human immunoglobulin (Ig) in serum. Several strategies to derive animals expressing human antibody repertoires have been successful. In rodents, gene loci on bacterial artificial chromo...
75 CitationsSource
#1Christina Vasalou (Novartis)H-Index: 2
#2Gabriel Helmlinger (Novartis)H-Index: 17
Last. Bruce Gomes (Novartis)H-Index: 2
view all 3 authors...
Antibody drug conjugates (ADCs) represent novel anti-cancer modalities engineered to specifically target and kill tumor cells expressing corresponding antigens. Due to their large size and their complex kinetics, these therapeutic agents often face heterogeneous distributions in tumors, leading to large untargeted regions that escape therapy. We present a modeling framework which includes the systemic distribution, vascular permeability, interstitial transport, as well as binding and payload rel...
45 CitationsSource
Cited By7
Newest
#1Pengxuan Zhao (HUST: Huazhong University of Science and Technology)H-Index: 2
#2Yuebao Zhang (OSU: Ohio State University)H-Index: 1
Last. Yizhou DongH-Index: 28
view all 6 authors...
Abstract Antibody drug conjugates (ADCs) normally compose of a humanized antibody and small molecular drug via a chemical linker. After decades of preclinical and clinical studies, a series of ADCs have been widely used for treating specific tumor types in the clinic such as brentuximab vedotin (Adcetris®) for relapsed Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma, gemtuzumab ozogamicin (Mylotarg®) for acute myeloid leukemia, ado-trastuzumab emtansine (Kadcyla®) for HER2-positiv...
11 CitationsSource
#1Corinna Duerr (LMU: Ludwig Maximilian University of Munich)H-Index: 1
#2Wolfgang Friess (LMU: Ludwig Maximilian University of Munich)H-Index: 43
Abstract The number of antibody-drug conjugates (ADCs) on the market is expected to multiply in the upcoming years. The main reason: this novel drug delivery system combines the benefits of the selectivity of the antibody and the potency of the cytotoxic agent. The interplay of the antibody, linker and payload, however, calls for a stable and unique formulation. In this review, the literature on the stability of marketed ADCs and the respective formulations are summarized and used as a basis to ...
10 CitationsSource
#1Lily Pei Yao Liu-Shin (UM: University of Miami)H-Index: 1
#2Adam Fung (Astellas Pharma)H-Index: 3
Last. Gayathri Ratnaswamy (Astellas Pharma)H-Index: 3
view all 4 authors...
ABSTRACTAntibody-drug conjugates (ADCs) that are formed using thiol-maleimide chemistry are commonly produced by reactions that occur at or above neutral pHs. Alkaline environments can promote disulfide bond scrambling, and may result in the reconfiguration of interchain disulfide bonds in IgG antibodies, particularly in the IgG2 and IgG4 subclasses. IgG2-A and IgG2-B antibodies generated under basic conditions yielded ADCs with comparable average drug-to-antibody ratios and conjugate distributi...
3 CitationsSource
#1Lily Liu-Shin (Astellas Pharma)H-Index: 1
#1Lily Liu-Shin (Astellas Pharma)H-Index: 3
Last. Gayathri Ratnaswamy (Astellas Pharma)H-Index: 3
view all 4 authors...
ABSTRACTCysteine-linked antibody-drug conjugates (ADCs) produced from IgG2 monoclonal antibodies (mAbs) are more heterogeneous than ADCs generated from IgG1 mAbs, as IgG2 ADCs are composed of a wider distribution of molecules, typically containing 0 – 12 drug-linkers per antibody. The three disulfide isoforms (A, A/B, and B) of IgG2 antibodies confer differences in solvent accessibilities of the interchain disulfides and contribute to the structural heterogeneity of cysteine-linked ADCs. ADCs de...
9 CitationsSource
The concept of exploiting the specific binding properties of monoclonal antibodies as a mechanism for selective delivery of cytotoxic agents to tumor cells is an attractive solution to the challenge of increasing the therapeutic index of cell-killing agents for treating cancer. All three parts of an antibody–drug conjugate (ADC)—the antibody, the cytotoxic payload, and the linker chemistry that joins them together—as well as the biologic properties of the cell-surface target antigen are importan...
107 CitationsSource
#1L. Nathan Tumey (Binghamton University)H-Index: 20
The clinical success of gemtuzumab ozogamicin, brentuximab vedotin and ado-trastuzumab emtansine has spurred significant investment into new ADC payloads that may expand the utility of ADC technology. Innovations in the past 5–10 years have resulted in the identification of new payloads that are overcoming resistance mechanisms, showing efficacy against slow growing tumors, and enabling the use of biomarkers to better understand ADC PK/PD relationships. Moreover, ADC technology is now enabling t...
2 CitationsSource
#1John M. Lambert (ImmunoGen, Inc.)H-Index: 52
#2Charles Q. Morris (ImmunoGen, Inc.)H-Index: 1
Attaching a cytotoxic “payload” to an antibody to form an antibody–drug conjugate (ADC) provides a mechanism for selective delivery of the cytotoxic agent to cancer cells via the specific binding of the antibody to cancer-selective cell surface molecules. The first ADC to receive marketing authorization was gemtuzumab ozogamicin, which comprises an anti-CD33 antibody conjugated to a highly potent DNA-targeting antibiotic, calicheamicin, approved in 2000 for treating acute myeloid leukemia. It wa...
130 CitationsSource