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Novel Payloads for Antibody-drug Conjugates

The development of antibody-drug conjugates or ADCs, has resulted in the need of developing novel compounds that can be used as payloads.

Enediynes, represented by are two different classes of antitumor compounds, including the nine-membered cyclic enediynes such as kedarcidin, LDM (Lidamycin, also known as C-1027), maduropeptin, and ten-membered cyclic enediynes such as calicheamicin, esperamycin, and dynemicin, were first discovered in 1987.

Since the discovery of calicheamicin and esperamicin, several more enediynes have been discovered as natural products in bacteria. Synthetic enediynes have also been designed to improve the functionality of the naturally occurring enediynes.

The distinctive strained nine- or ten-member ring system comprising a Z-carbon-carbon double bond and two carbon-carbon triple bonds, are usually arranged with the latter two flanking the former.

Produced by a variety microorganism, including of Actinomadura verrucosospora and Micromonospora echinospora, these compounds present intricate mechanisms of action as well as remarkable biological activities.

Generally speaking, enediynes, which are potent cytotoxic agents (IC50 values in the picomolar range) which damagers of DNA causing single and double strand cuts, are too toxic for clinical use. The potency of these compounds is attributed to their ability to bind to DNA and undergo a Bergmann rearrangement (also known as Bergman cyclization*) in which the strained ring system is converted into a highly reactive 1,4-benzenoid diradical, which damages the DNA by abstracting hydrogens from it.

When the diradical is generated near DNA, it abstracts hydrogen atoms from the sugar backbone of the DNA molecule, which results in single and double strand lesions.

Although this makes enediynes these very toxic, their potent activity can be beneficial when targeting the DNA of cancerous tumors.

Interestingly, most endiynes offer potent activity against the proliferation of various cancer cells including those with resistance to other chemotherapeutic drugs. [1]

Antibody-drug conjugate
The biological evaluation of a select number of enediynes and enediyne analogues has led to the identification of a variety of novel compounds with low picomolar potencies against certain cancer cell lines. Still too toxic as a single agent, these compounds have been used as payloads for antibody-drug conjugates.

Calicheamicin, first discovered in the mid-1980’s, a phenomenally active compound, extremely active against tumor cells was synthesized it in 1992. Linking the compound to an antibody, scientists were able to deliver it to certain cancer types selectively without the side effects of the very toxic compound.

Among the developed therapeutic agents is gemtuzumab ozogamicin (Mylotarg®; Pfizer/Wyeth), an antibody-drug conjugate in which calicheamicin was conjugated with recombinant humanized IgG4 kappa antibody, which binds to CD33 antigens expressed on the surface of leukemia blasts. The drug was approved for the treatment of myeloid leukemia.

Another therapeutic agent in this class is CMC-544 (inotuzumab ozogamicin; Blincyto®; Pfizer/Wyeth) a calicheamicin-conjugated anti-CD22 monoclonal antibody, a highly potent cytotoxic enediyne antibiotics that bind DNA in the minor groove and cause double strand DNA breaks (dsDNAB) leading to cell death. This agent was approved in 2016 for the treatment of adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

But not all calicheamicin-conjugated have been successfully developed. CMB-401, for example, an antibody-drug conjugate consisting of the monoclonal antibody hCTM01 directed against polymorphic epithelial mucin covalently bound to the cytotoxic antibiotic calicheamicin by an amide linker.

Although CMB-401 showed targeted killing of MUC1-expressing cells in vitro and produced pronounced dose-related antitumor effects over an eightfold dose range against an MUC1-expressing ovarian carcinoma xenograft (OvCar-3), the drug did not meet the criteria for partial remission. Based on published efficacy of conjugates that deliver calicheamicin via hybrid (bifunctional) linkers [e.g. gemtuzumab ozogamicin, in acute myeloid leukemia, the scientists hypothesize that the amide linker used in CMB-401 may have contributed to its failure to induce a partial response. [2]

Rice University scientists have improved the production of a potent antitumor antibiotics from the enediyne class known as uncialamycin.

Image 1.0: Uncialamycin

, which depending on the epimer and cell line or subline has shown activity against several ovarian tumor cell lines with IC50 values ranging from 9 × 10–12 to 1 × 10–10, has been recognized to be among the rarest and most potent, yet one of the structurally simpler agents, making it attractive for chemical synthesis and potential applications in biology and medicine.

Rice University scientists have developed synthetic strategies and technologies and applied these to the synthesis of a number of uncialamycin analogues. Equipped with suitable functional groups for conjugation to antibodies, uncialamycins are suitable as a payload for antibody-drug conjugates and other delivery systems.

The potency, efficacy and mechanism of action of uncialamycin analogs was demonstrated by scientists at Bristol-Myers Squibb Research & Development with the development of a highly potent uncialamycin analog with a valine-citrulline dipeptide linker conjugated to an anti-mesothelin monoclonal antibody through lysines to generate a novel antibody-drug conjugate. This investigational drug demonstrated subnanomolar potency (IC50 = 0.88 nM, H226 cell line) in in vitro cytotoxicity experiments with good immunological specificity to mesothelin-positive lung cancer cell lines. [3]

Lidamycin or LDM (original named C-1027, Lidamycin was isolated from the broth filtrate of Streptomyces globisporus C1027 ) is an antitumor antibiotic which shows extremely potent cytotoxicity toward human cancer cells with IC50 values 1000-fold lower than that of Adriamycin in vitro.

In clinical trials, the compound, which consist of 2 independent parts, an apoprotein moiety (LDP) which forms a hydrophobic pocket to protect the chromophore and a non-protein active enediyne chromophore (AE) responsible for the extremely potent bioactivity, showed remarkable inhibition on a panel of transplantable tumors in mice.

Lidamycin can induce cell damage including apoptosis, cell cycle arrest, and DNA double-strand breaks and is considered to be a desirable cytotoxic payload for antibody-drug conjugates due to its extremely potent cytotoxicity to cancer cells.[4]

Scientists at the Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China, have developed anti-CD30-LDM, a novel ADC which consists of the intact chimeric antibody directed against CD30 and Lidamycin.

The investigational anti-CD30-LDM agent shows attractive tumor-targeting capability and antitumor efficacy both in vitro and in vivo and could be a promising candidate for the treatment of CD30+ lymphomas, including Hodgkin’s lymphoma (HL) and anaplastic large-cell lymphoma (ALCL).[5]

Thailanstatin A
Today, more than 60% of ADCs in clinical trials employ microtubule inhibitors (auristatins or MMAE/MMAF and maytansinoids or DM1/DM4) as their payloads. [6]

Scientists looking for cytotoxic payloads beyond the microtubule inhibitor class, a potent payload for lysine conjugated antibody-drug conjugate called Thailanstatin A was introduced.

A number of variations of Thailanstatin A, a natural product analog of spliceostatin, a complex of proteins and ribonucleoproteins that regulate DNA splicing originally isolated from burkholderia thailandensis bacteria, are being investigated as a potential payload.
The novel, extremely potent, compound fights cancer by inhibiting the machinery in the cell that edits messenger RNA after transcription from DNA but before its translation into proteins.

Scientists at Pfizer’s Oncology-Rinat Research & Development and Pfizer’s Drug Safety Research and Development, in Pearl River, New York prepared a series of thailanstatin-antibody conjugates in order to evaluate their potential in the treatment of cancer.

After exploring a variety of linkers, they found that the most potent antibody-drug conjugates were derived from direct conjugation of the carboxylic acid-containing payload to surface lysines of the antibody (also known “linker-less” conjugates).

Activity of these lysine conjugates was correlated to drug-loading, a feature not typically observed for other payload classes. The thailanstatin-conjugates were potent in high target expressing cells, including multidrug-resistant lines, and inactive in nontarget expressing cells.

The researchers noted that the exposure of the thailanstatin-conjugates was sufficient to result in excellent potency in a gastric cancer xenograft model at doses as low as 1.5 mg/kg that was superior to the clinically approved ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche). [7]

Scientists at Pfizer’s showed that there is a high dependence of the potency of thailanstatin based antibody-drug conjugates with the site of conjugation. They showed that site-specific thailanstatin antibody-drug conjugates were very efficacious in an in vivo gastric cancer tumor xenograft model thus demonstrating the suitability of this novel class of payload for consideration in next-generation site-specific ADC programs.

A library of payloads
The development of novel, potent, payloads for antibody-drug conjugates with different mechanisms of action, has, over the last decades, challenged synthetic organic chemists to develop a library of potential payloads designed to address the medical needs for the various types of cancers.

In a recent review, scientists at Rice University describe their work of total synthesis of natural and designed molecules of the calicheamicin, uncialamycin, tubulysin, trioxacarcin, epothilone, shishijimicin, namenamicin, thailanstatin, and disorazole families of compounds. In their review they demonstrate how these novel compounds led to the discovery of analogues of higher potencies, yet some of them possessing lower complexities than their parent compounds as potential payloads for antibody-drug conjugates.[8]

These compounds and others like them may serve as powerful payloads for the development of antibody-drug conjugates intended for personalized targeted cancer therapy.

[1] Abdel-Magid AF. New synthetic enediynes and their conjugates may provide effective treatment for cancer. ACS Med Chem Lett. 2013 Sep 20;4(11):1018-9. doi: 10.1021/ml400362m. eCollection 2013 Nov 14.
[2] Chan SY, Gordon AN, Coleman RE, Hall JB, Berger MS, Sherman ML, Eten CB, Finkler NJ. A phase 2 study of the cytotoxic immunoconjugate CMB-401 (hCTM01-calicheamicin) in patients with platinum-sensitive recurrent epithelial ovarian carcinoma. Cancer Immunol Immunothery 2003 Apr;52(4):243-8. Epub 2003 Feb 26.)
[3] Chowdari NS, Pan C, Rao C, Langley DR, Sivaprakasam P, Sufi B, Derwin D, Wang Y, et al. Uncialamycin as a novel payload for antibody drug conjugate (ADC) based targeted cancer therapy. Bioorg Med Chem Lett. 2018 Dec 11. pii: S0960-894X(18)30955-7. doi: 10.1016/j.bmcl.2018.12.021. [Epub ahead of print]
[4] Zhang Y, Liu R, Fan D, Shi R, Yang M, Miao Q, Deng ZQ, Qian J, Zhen Y, Xiong D, Wang J. The novel structure make LDM effectively remove CD123+ AML stem cells in combination with interleukin 3. Cancer Biol Ther. 2015;16(10):1514-25. doi: 10.1080/15384047.2015.1071733. Epub 2015 Jul 17.
[5] Wang R, Li L, Zhang S, Li Y, Wang X, Miao Q, Zhen Y. A novel enediyne-integrated antibody-drug conjugate shows promising antitumor efficacy against CD30+ lymphomas. Mol Oncol. 2018 Mar;12(3):339-355. doi: 10.1002/1878-0261.12166. Epub 2018 Jan 26.
[6] Fu Y, Ho M. DNA damaging agent-based antibody-drug conjugates for cancer therapy. Antib Ther. 2018 Sep;1(2):33-43. doi: 10.1093/abt/tby007. Epub 2018 Aug 30.
[7] Puthenveetil S, Loganzo F, He H, Dirico K, Green M, Teske J, Musto S1, Clark T, et al. Natural Product Splicing Inhibitors: A New Class of Antibody-Drug Conjugate (ADC) Payloads. Bioconjug Chem. 2016 Aug 17;27(8):1880-8. doi: 10.1021/acs.bioconjchem.6b00291. Epub 2016 Jul 28.
[8] Nicolaou KC, Rigol S. Total Synthesis in Search of Potent Antibody-Drug Conjugate Payloads. From the Fundamentals to the Translational. Acc Chem Res. 2018 Dec 21. doi: 10.1021/acs.accounts.8b00537. [Epub ahead of print]

* The Bergman cyclization or Bergman reaction or Bergman cycloaromatization is an organic reaction and more specifically a rearrangement reaction taking place when an enediyne is heated in presence of a suitable hydrogen donor.

Last Editorial Review: January 3, 2019

Featured Image: Laboratory assistant. Courtesy: © 2010 – 2019 Fotolia. Used with permission. Image 1.0: Uncialamycin Courtesy: © 2010 – 2019 Rice University. Used with permission.

Copyright © 2019 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.



Are Small-Format Drug Conjugates a Viable ADC Alternative Solid Tumors?

Antibody-drug conjugates or ADCs are complex immunoconjugates. They are designed to selectively deliver a small-molecules cytotoxic payload to cancer cells. Directed to specific tumor antigens, antibody-drug conjugates consist of a monoclonal antibody linked via a molecular linker to a cytotoxic agent. [1]

In addition to the targeting monoclonal antibody, the linker technology is crucial. The linker needs to be sufficiently stable in circulation to allow the payload to remain attached to the antibody while, at the same time should allow efficient release of an active cell-killing agent after the antibody-drug conjugate is internalized.

After binding to a specific antigen on the surface of cancer cells, the ADC is internalized where, inside the cell, the cytotoxic payload is released to kill the malignant cell. Today, these cytotoxic payloads include two microtubule-disrupting agents maytansinoids and auristatins as well as a DNA-targeting antibiotic, calicheamicin.[2]

These payloads are included in a number of antibody-drug conjugates approved by the U.S. Food and Drug Administration (FDA). These agents include brentuximab vedotin (Adcetris®; Seattle Genetics) for Hodgkin and anaplastic large cell lymphoma, ado-trastuzumab emtansine (Kadcyla®, also known as T-DM1; Genentech/Roche) for HER2-positive metastatic breast cancer, gemtuzumab ozogamicin (Mylotarg®; Pfizer) for acute myeloid leukemia and inotuzumab ozogamicin (Besponsa®; Pfizer) for the treatment of acute lymphoblastic leukemia.

In addition, nearly 180 other agents are in development – from early stage discovery to advanced stages of clinical development. These novel agents including sacituzumab govitecan for breast cancer, mirvetuximab soravtansine for ovarian cancer, rovalpituzumab tesirine (Rova-T) for lung cancer, depatuxizumab mafodotin for glioblastoma, and oportuzumab monatox for bladder cancer.

While today four antibody-drug conjugates are successfully implemented in clinical strategies, the majority of these ADC are used in liquid, hematological, cancers. The number of antibody-drug conjugates in the treatment of solid, non-hematological, tumor is limited. Most ADCs focusing on solid tumors have not progressed beyond Phase I clinical trials, suggesting that there is an unmet need to optimize additional factors governing translational success.[3]

The first approved antibody-drug conjugates were approved for the treatment of hematologic malignancies. Gemtuzumab ozogamicin is an anti-CD33 antibody conjugated via an acid–labile linkage to calicheamicin. The second approved antibody, brentuximab vedotin, included an anti-CD30 antibody conjugated via a cleavable valine-citrulline (vc) dipeptide linker to the microtubule-disrupting agent monomethyl auristatin E (MMAE).

The first antibody-drug conjugate to be approved for the treatment of non- hematologic, solid tumors was ado-trastuzumab emtansine. This antibody-drug conjugate was developed by conjugating the sulfhydryl group of maytansinoid DM1 to lysine amino groups of the anti-human epidermal growth factor receptor 2 (HER2) antibody, trastuzumab, via reaction with the bifunctional non-cleavable linker, succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC).

While antibody-drug conjugates have been successfully included in therapeutic strategies for the treatment of patients with various forms of malignancies, there is a growing number of agents for which clinical development programs have been discontinued because of insufficient activity at the maximum doses that can be tolerated upon repeat administration. This is especially the case in solid, non-hematological, tumors.

Alternatived to current technologies
Current antibody-drug conjugate-technologies focus on large, whole immunoglobulin formats. Many of these ADCs have been developed with site-specifically conjugated payloads with a DAR (drug to antibody ratio) of 2 or 4.

As discussed above, the majority of ADCs have not had much success in the treatment of solid, non-hematological, tumors.  As result, leading researchers are now exploring alternatives, smaller formats-drug conjugates, including single domain antibody fragment–drug conjugates, single-chain formats such as the scFv, diabodies (head-to-tail dimer of a scFv) and small immuno-proteins (SIPs-scFvs dimerised using a CHε4-domain, approximately half the size of an monoclonal antibody), from 80 kDa to around 1 kDa in total size, which have better penetrating properties as well as more rapid pharmacokinetics (PK).

Discussed in a review by Mahendra P. Deonarain, Gokhan Yahioglu and colleagues, working for Antikor Biopharma, in Stevenage Herts, United Kingdom, and the UK Department of Chemistry, Imperial College London, London, United Kingdom, published in the June 2018 edition of Antibodies (Volume 7, Issue 2), both practical studies and theoretical reviews support the idea that smaller antibody fragments may have faster diffusion and extravasation coefficients and penetrate tumors more rapidly than monoclonal antibodies.[4]

In general, these alternative agents are potent in vitro, particularly the more recent ones incorporating  auristatins or maytansinoids. However, due to the more rapid clearance, the potency profile of these smaller compounds changes when being tested  in vivo. Strategies to manipulate the PK properties, while, at the same time, retaining the more effective tumor penetrating properties, may, as being discussed by Deonarain and colleagues, make small-format drug conjugates viable alternative therapeutics to the more established antibody-drug conjugates.

Last Editorial Review: July 22, 2018

Featured Image: Laboratory Glass works. Courtesy: © 2010 – 2018. Fotolia Used with permission. F

Copyright © 2018 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.


Glythera and Cancer Research UK Collaborate in the Development of “Next-Gen” Antibody-drug Conjugates

Cancer Research UK and Glythera, a company developing the “next-gen” antibody-drug conjugates or ADCs have agreed that Glythera receives exclusive, worldwide rights, to the charity’s novel cyclin-dependent kinases 11/ CDK11 inhibitor payload series for the development of multiple ADCs. The novel agents will be using Glythera’s proprietary PermaLink® conjugation platform.

The company’s technology involves a controlled, stable conjugation platform composed of a portfolio of linker designs, which can be used for the selective and stable functionalization and conjugation of various cytotoxic payloads to proteins and peptides.

Cyclin-dependent kinases
One of the common features of many cancer types is the over-expression and/or hyperactivation of cyclin-dependent kinases or CDKs. They are a family of protein kinases first discovered for their role in regulating the cell cycle – and binds to a regulatory protein called a cyclin.

CDKs are relatively small proteins. Their molecular weights range from 34 to 40 kDa, and they contain little more than the kinase domain. Only the cyclin-CDK complex is an active kinase, and without binding to a cyclin, a CDK has virtually no kinase activity.

Recent research has shown that an important role in tumor cell proliferation and growth by controlling cell cycle, transcription, and RNA splicing.[1]

For example, while CDK11 has previously has not been implicated  in ovarian cancer, researchers have found  that its expression is upregulated in human ovarian cancer tissues and associated with malignant progression. Furthermore, metastatic and recurrent tumors generally have significantly higher CDK11 expression when compared with the matched, original primary tumors.

CDK activation
Each individual CDK can be activated following binding with their corresponding cyclin partner, and following binding each kinase in this family is, in a coordinated way, responsible for particular aspects of the cellular events. Aberrant expression or altered activity of distinct CDK complexes results in escape of cells from the cell cycle control, which, in turn, leads to malignant transformation.

One of the cyclin-dependent kinases, CDK11, a serine/threonine protein kinase in the family of CDKs, has a critical roles in cancer cell growth and proliferation. Scientists believe that a number of genetic and epigenetic events cause universal overexpression of CDK11 in human cancers. In turn, CDK11 interacts with numerous proteins in transcription and RNA processing (Hsp90; cyclin L1, L2, D3, CK2, etc.) and is encoded by two highly homogenous genes, CDC2L1 (CDK11B) and CDC2L2 (CDK11A) – genes that produce 3 isoforms which are associated with distinct cellular functions.

In turn, inhibition of CDK11 leads to cancer cell death and apoptosis. The available evidence suggested that CDK11 may be a novel and promising therapeutic target for the treatment of cancers.[2]

Optimizing cytotoxins
Based on the agreement, Glythera and Cancer Research UK will select and optimize a number of cytoxins from the available inhibitor payload series for development in multiple antibody-drug conjugates. Following selection, Glythera will then progress these novel ADC contructs, optimized according to cancer cell-kill profiles, for difficult-to-treat tumors.

Glythera is currently evaluating a range of clinically important antibody targets and intends to identify its first clinical antibody-drug conjugate candidate by 2019.

Successful Collaboration
This agreement between the two companies follows a successful period of collaboration during which the viability of selected low molecular weight CDK11 molecules was demonstrated in relevant ADC models.

The CDK11 inhibitor program has identified a series of low molecular weight, synthetically tractable compounds which potently inhibit and are selective against other kinase targets. The series demonstrates highly potent anti-proliferative activity in dividing and non-dividing tumour cells and represents an exciting approach for antibody-drug conjugates.

Milestone Payments
Cancer Research UK will receive an undisclosed up-front fee, milestone payments on programme success for each resulting ADC, and royalties on worldwide product sales. Glythera is responsible for the development, manufacturing and commercialization of any ADC products resulting from the agreement.

“This collaboration highlights the success of our drug discovery approach in translating the most promising early stage research into new cancer treatments,” Hamish Ryder, director of Cancer Research UK’s Therapeutic Discovery Laboratories, a wholly owned subsidiary of Cancer Research UK which pursues drug discovery research in themed alliance partnerships and delivers varied commercial partnering arrangements.

“We’re excited to work with Glythera to identify and advance the very best novel agents and develop targeted treatments for cancer patients. By continuing to bring together industry and world leading academics in this field, we hope to transform the outlook for people with cancers that are the hardest to treat,” Ryder added.

“I am delighted that Glythera is working with Cancer Research UK as we look to identify and develop CDK11 inhibitor payloads and antibody conjugates to combat difficult-to-treat solid tumours and improve the lives of patients living with cancer,” Dave Simpson, Chief Executive Officer at Glythera concluded.

Last Editorial Review: September 28, 2017

Featured Image: science laboratory test tubes. Courtesy: © 2017. Fotolia. Used with permission.

Copyright © 2017 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.


Selenomab-drug Conjugates: Delivering Strong Results in Treating Cancers

Scientists from the Florida campus of The Scripps Research Institute (TSRI), one of the world’s largest independent, not-for-profit organizations focusing on research in the biomedical sciences, have developed a new drug delivery method that produces strong results in treating cancers in animal models, including some hard-to-treat solid and liquid tumors.

The study, led by Christoph Rader, Ph.D. Associate Professor Department of Immunology and Microbiology at TSRI, was published March 16, 2017, online ahead of print in the journal Cell Chemical Biology.[1]

The new method involves a class of pharmaceuticals known as antibody-drug conjugates or ADCs, which include some of the most promising next-generation antibody therapeutics for cancer. ADCs can deliver a cytotoxic payload in a way that is remarkably tumor-selective. So far, three ADCs have been approved by the U.S. Food and Drug Administration (FDA), but neither attaches the drug to a defined site on the antibody.

Photo 1.0. Research Associate Xiuling Li (left) and Associate Professor Christoph Rader led the study on the Florida campus of The Scripps Research Institute. (Photo by Junpeng Qi.)

“We’ve been working on this technology for some time,” Rader said. “It’s based on the rarely used natural amino acid selenocysteine, which we insert into our antibodies. We refer to these engineered antibodies as selenomabs.”

Antibodies are large immune system proteins that recognize unique molecular markers on tumor cells called antigens.

On their own, Rader noted, antibodies are usually not potent enough to eradicate cancer. However, their high specificity for antigens makes them ideal vehicles for drug delivery straight to tumor cells.

“We now show for the first time that selenomab-drug conjugates, which are ADCs that utilize the unique reactivity of selenocysteine for drug attachment, are highly precise, stable and potent compositions and promise broad utility for cancer therapy.”

Inhibiting growth
Along with its potency, Rader noted, the ADC’s stability is critical to its effectiveness. The researchers found that their new ADCs showed excellent stability in human blood in vitro and in circulating blood in animal models. Moreover, the new ADCs were highly effective against HER2 breast cancer, a particularly difficult cancer to treat, and against CD138 multiple myeloma. Importantly, the ADCs did not harm healthy cells and tissues.

“The selenomab-drug conjugate significantly inhibited the growth of an aggressive breast cancer,” explained TSRI Research Associate Xiuling Li, first author of the study. “Four of the five mice tested were tumor-free at the end of the experiment, a full six weeks after their last treatment.” [2]

The researchers plan to investigate similar ADCs going forward. Rader, along with TSRI Professor Ben Shen, was recently awarded $3.3 million from the National Cancer Institute of the National Institutes of Health to test highly cytotoxic natural products discovered in the Shen lab using selenomabs as drug delivery vehicles.

The study was supported by the National Institutes of Health, the Intramural Research Program of the National Cancer Institute, the Lymphoma Research Foundation, the Klorfine Foundation and the Holm Charitable Trust.

Last Editorial Review: March 17, 2017

Featured Image: Sunrise in Miami. Courtesy: © 2017 Fotolia. Used with permission. Photo 1.0. Research Associate Xiuling Li (left) and Associate Professor Christoph Rader led the study on the Florida campus of The Scripps Research Institute. Courtesy: © 2017 Junpeng Qi. Used with permission.

Copyright © 2017 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.


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