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Site-Specific Antibody Conjugation for ADC and Beyond
Published in Raj Bawa, János Szebeni, Thomas J. Webster, Gerald F. Audette, Immune Aspects of Biopharmaceuticals and Nanomedicines, 2019
As one of the targeted therapies or the “magic bullet” proposed by Paul Ehrlich more than a century ago [12], the ADC is the targeted delivery of a highly cytotoxic drug for selective (as opposed to systemic) chemotherapy, resulting in an improved therapeutic index and enhanced efficacy relative to traditional chemotherapies or naked monoclonal antibodies. Thus, this unique format would allow the use of certain chemotherapeutic drugs that are too potent or toxic to be applied systemically. Since these cytotoxins need to be delivered into the tumor cells targeting intracellular microtubules or DNA, the chemotherapeutic drugs carrying antibodies should be efficiently internalized into lysosomes once binding to the antigen on the tumor surface (Fig. 4.1). Within the lysosome, cytotoxins would be efficiently released from antibodies through proteolytic cleavage or disulfide reduction before they diffuse into the cytoplasm for cytotoxicity. Although the ADC idea has been around for decades, the medicine used in clinics was not available until 2000 with the regulatory approval of the first ADC, gemtuzumab ozogamicin (anti-CD33 ADC). Currently, four ADCs have been approved by regulatory agencies for cancer treatment: gemtuzumab ozogamicin (anti-CD33 ADC) for acute myelogenous leukemia (AML), brentuximab vedotin (anti-CD30 ADC) for treating anaplastic large cell lymphoma/Hodgkin’s lymphoma, trastuzumab emtansine (Anti-HER2 ADC) for advanced HER2 (human epidermal growth factor receptor 2)-positive breast cancer, and inotuzumab ozogamicin (anti-CD22 ADC) for the treatment of relapsed or refractory acute lymphoblastic leukemia (ALL) [13–22].
Production of Life-Saving Drugs from Marine Sources
Published in Prasenjit Mondal, Ajay K. Dalai, Sustainable Utilization of Natural Resources, 2017
Gemtuzumab ozogamicin (trade name Mylotarg®, Pfizer/Wyeth) was the first ADC to receive marketing approval in 2001 by U.S. FDA for the treatment of acute myelogenous leukemia. However, it was withdrawn from market in June 2010 by the sponsor due to the absence of significant benefit and safety reasons in post-approval phase III of clinical trial. Trastuzumab emtansine (Herceptin®, Genentech and Roche), an ADC composed of trastuzumab linked via a noncleavable linker to DM1, was approved in February 2013 for the treatment of HER2-positive refractory/relapsed mBC. Later, it was withdrawn from market. As a result, only one ADC Brentuximab vedotin (trade name: Adcetris, marketed by Seattle Genetics and Millennium/Takeda) is in the market.
Design and Delivery of Antibody–Drug Conjugates
Published in Sandeep Nema, John D. Ludwig, Parenteral Medications, 2019
The drugs attached to the antibody are also referred to as the payload. Payloads are typically small-molecule chemo-toxic agents that have shown some initial promise in in vitro and in vivo cancer models. A vast majority of chemotoxins are either antimitotic (e.g., maytansinoid, auristatin) or DNA-damaging agents (e.g., calicheamicin, doxorubicin). Representative payloads in recently approved ADCs are shown in Figure 16.3. Currently, the two approved ADCs in the market are based on antimitotic agents, while the first approved ADC (gemtuzumab ozogamicin) was based on a calicheamicin derivative. Most of these payloads have unacceptable safety profiles when administered alone, and hence, there is a need for targeted delivery via the ADC platforms. Some of the important chemical attributes of these payloads or drugs include potency in sub-nanomolar concentrations, solubility, conjugatability, and stability. The synthesis and characterization of these small-molecule toxins are not in scope for this chapter. Though much smaller in size than an antibody, upon conjugation to the mAb, the small-molecule payload can significantly impact the overall solubility and stability of the ADC. The solubility and stability of the ADC may be limited based on DAR. Higher DARs may essentially have higher hydrophobicity and associated solubility challenges in aqueous media.9 While higher DARs may lead to better in vitro potency, research has shown that higher DARs have suboptimal in vivo properties due to faster clearance.10 In order to be an effective cancer treatment, it is also recommended that extremely potent molecules with broad therapeutic index be chosen for further development. Interestingly, a moderately toxic irinotecan derivative targeting Trop-2 is also under clinical development for various cancers.11
Advances of engineered extracellular vesicles-based therapeutics strategy
Published in Science and Technology of Advanced Materials, 2022
Hiroaki Komuro, Shakhlo Aminova, Katherine Lauro, Masako Harada
The use of monoclonal antibodies for cancer therapy has been of great interest and development [263–265]. Antibodies act to obtain specific targeting of drugs in the form of antibody-drug conjugates (ADCs). They have sufficient antitumor activity to be approved and used in clinical practice. However, there are concerns that chemically binding antibodies to drugs may lead to drug inactivation and problems with drug release after the conjugate is taken up by cancer cells. Modified antibodies on the EVs membrane may circumvent these problems because the drug is encapsulated by the EV rather than the drug and the antibody is covalently bound. There is no set method for conjugating antibodies to EVs, but some methods used before include fusing C1C2 to an anti-EGFR antibody as seen in Koojimans et al [134]. Alternatively, Li et al. used a chemical approach that involved coating the EVs with antibodies by isolating them from A33 positive LIM1215 cells. The researchers then loaded the EVs with therapeutic doxorubicin and then combined them with SPIONS that were coupled with A33 antibodies [266]. The aim was that the A33 antibodies would bind to A33 positive EVs to achieve A33 targeting, as A33 is highly expressed in colorectal cancers. Pham et al. in contrast did not use a genetic or chemical approach to surface engineering antibodies on EVs, but rather an enzymatic method [267]. The researchers used Sortase A and OaAEP1, protein ligating enzymes, to conjugate EVs with anti-EGFR antibodies to achieve targeted delivery to EGFR positive lung cancer cells and mice. Therefore, antibody use in conjugation with EVs shows a lot of potential for targeted drug delivery.