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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.



ADC Biotechnology Secures Funding for Strategic move into Downstream Formulation and Fill Finish

UK-based ADC Biotechnology, an innovative biotechnology company developing new process technology to speed, simplify and significantly lower the production costs of antibody-drug conjugates, has secured additional funding of £2.5 million (U.S. $ 3.2 million) from existing investors and company management.

The additional funds will be use to finance the company’s strategic move into downstream formulation and fill finish capabilities.

“We are delighted to have obtained this additional injection of funds that will be used to support the company’s strategic aspirations, including conceptual design of a downstream formulation and filling operation to complement our existing bioconjugation operations at the Deeside facility,” said Charlie Johnson, Chief Executive Officer of ADC Biotechnology.

Photo 1.0: Charlie Johnson, CEO of ADC Biotechnology.

“We are also looking to fully exploit our core Lock-Release technology to create a transformative manufacturing paradigm that will significantly streamline ADC manufacturing supply chains,” he added.

The proprietary Lock-Release technology developed by ADC biotechnology is a fast, simple, cost efficient and robust system to guarantee ADCs of a consistently high quality and purity. The technology is the only commercially available system that controls aggregation at source, is scaleable and capable of meeting cGMP regulatory requirements required to produce materials for use in human clinical trials.

Additional funding
This follows the announcement last April in which the company unveiled that it had secured funding from Downing LLP to bolster the company’s marketing and new business drive for quicker penetration into the main US market.

“The investment has been secured in response to strong supportive trends from the ADC development sector and will be put to good use in our planned strategy to further differentiate our company’s unique technology and service offering,” Johnson noted:

The investment syndicate consists of Maven Capital Partners, Seneca Partners, the Development Bank of Wales and Downing LLP.

Editorial Review: November 18, 2018

Featured Image: Funding Contract. Courtesy: © 2010 – 2018 Fotolia. Used with permission.

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.


Four Ways to Show Nonobviousness of ADC Inventions

When the first antibody-drug conjugate (ADC) was approved by the U.S. Food and Drug Administration (FDA) in 2000,[1] only a handful of patent applications claiming ADCs had been published.[2] As research continues to progress and the scientific community’s appreciation for the power of ADCs has grown, so have the numbers. FDA has now approved at least four ADCs,[3] and hundreds more are in development.[4] The number of patent applications has also grown, with the U.S. Patent and Trademark Office (USPTO) publishing over two hundred patent applications with claims to ADC inventions in the last two years alone.[5]

But filing an application with the USPTO does not guarantee that a patent will be obtained. Among other requirements, inventions worthy of U.S. patent protection must not have been obvious to a person of ordinary skill in the art at the time of invention (or, under current U.S. patent law, at the time the patent application was filed). In considering whether an invention would have been obvious, the USPTO will consider what was already known in the art, how the claimed invention differs from what was already known, and whether the differences would have been obvious. An invention may be deemed nonobvious if, for example, there was no motivation to modify what was known or no reasonable expectation of success in achieving the claimed invention, or if the invention enjoys commercial success or demonstrates results that would have been unexpected at the time of invention.

Four ways to demonstrate nonobviousness of an ADC invention are to show that (1) the claimed antibody, drug, or linker was not previously known; (2) a person having ordinary skill in the art would not have been motivated to modify known components to achieve the claimed ADC; (3) the skilled artisan would have had no reasonable expectation of success; or (4) the claimed ADC demonstrates unexpected results. These types of arguments have been presented to the USPTO in ADC-based patent applications, often in combination with each other and with amendments to the pending claims.

Provided below are three examples of patents that issued after such nonobviousness arguments were made to the USPTO: U.S. Patent Nos. 8,603,483 (the ’483 patent); 9,308,278 (the ’278 patent); and 9,850,312 (the ’312 patent). Companies seeking patent protection for their own ADC inventions should consider these and other examples when developing their own nonobviousness positions. The authors have not independently analyzed the obviousness of the claims discussed below, but provide these merely as examples of strategies used to secure allowance of claims directed to ADCs before the USPTO. Readers are encouraged to seek legal counsel in considering their own ADC inventions and these examples.

Example 1: Arguments of No Motivation, No Reasonable Expectation of Success, and Unexpected Results During the Prosecution of U.S. Patent No. 8,603,483 [6]

The USPTO issued the ’483 patent to Janssen Biotech, Inc. and ImmunoGen, Inc. on December 10, 2013, with claims to ADCs, pharmaceutical compositions comprising the ADCs, articles of manufacture comprising the ADCs, methods of producing the ADCs, methods of treating cancer using the ADCs, and methods of inhibiting the growth of cancer cells using the ADCs. For example, independent claim 1 is as follows:

1. An antibody-drug conjugate of the formula:

wherein the antibody is a human alphaV integrin specific antibody, and said antibody is capable of being internalized by a cell expressing said alphaV integrin, and wherein said antibody comprises (i) all of the heavy chain complementary determining region (CDR) amino acid sequences of CNTO 95 as shown in SEQ ID NOS: 1, 2, and 3, and (ii) all of the light chain CDR amino acid sequences of CNTO 95 as shown in SEQ ID NOS: 4, 5, and 6; and wherein the maytansinol is esterified at C-3; R1 and R2 are Me; X1 and X2 are H[;] n is 2; p is 2; and m is 3-4, and the pharmaceutically acceptable salts and esters thereof.

On June 3, 2011, during prosecution of the application that issued as the ’483 patent, the USPTO examiner rejected the then-pending claims for obviousness over combinations of four references. According to the examiner, the first reference taught an immunoconjugate comprising the antibody of CNTO 95 linked to a cytotoxin, the second reference taught that blockade of integrin receptors by CNTO 95 inhibited the growth of new blood vessels in vitro and growth of human melanoma tumors in nude mice, and the third reference taught that CNTO 95 has antitumor and antiangiogenic activity in vivo.

The examiner wrote that the invention of the then-pending claims differed from these teachings only by the recitation that the conjugate has the formula of [C‑L]m‑A, wherein C is DM4 (R1 and R2 are Me and n=2). According to the examiner, the fourth reference taught a conjugate comprising the huMy9-6 monoclonal antibody chemically coupled to maytansinoid DM4 via an N-succinimidyl 4-(2-yridyldithio)butanoate, and it would have been obvious to one of ordinary skill in the art to substitute hyMy9-6 antibody with the CNTO-95 antibody.

In a response dated December 2, 2011, the applicant amended the claims and argued that one of skill in the art at the time of invention would not have been motivated to substitute the CNTO 95 antibody for the huMy9-6 monoclonal because the two antibodies are “very different.” The applicant also argued that an artisan would not have reasonably expected success in substituting one antibody with another antibody that is structurally and chemically very different. In addition, the applicant argued that the art did not suggest that conjugating an anti-alphaV antibody to a cytotoxic drug would provide an important improvement or advantage over the use of the unconjugated CNTO 95 antibody. In support of the arguments, the applicant submitted three declarations. In the first, a named inventor declared that the effectiveness of the CNTO 95-maytansinoid conjugate CNTO 365 in treating tumors was surprising. In the second, a scientist declared that an artisan would not have been motivated to substitute huMy9-6, a highly selective antibody, with CNTO 95, an antibody with high reactivity with normal tissue, and would not have had a reasonable expectation of success. In the third, another scientist provided results from a phase I clinical study using CNTO 365, which the applicant argued showed unexpected and surprisingly low toxicity.

On January 12, 2012, the USPTO examiner maintained the obviousness rejections of the then-pending claims over the same art. The examiner wrote that while CNTO 95 was unexpectedly well tolerated in human clinical trials, the unexpected results did not overcome clear and convincing evidence of obviousness.

In a response dated September 12, 2012, the applicant amended the claims to “closely encompass the CNTO 365 conjugate described and tested in the application,” and argued that the claimed conjugates demonstrated unexpected results because they had a more than four-fold lower EC50 in toxicity studies relative to even other CNTO 95 conjugates. The USPTO examiner issued a notice of allowance, and then the ’483 patent issued on December 10, 2013. The examiner wrote that the amended claims were allowed because CNTO 365 was shown to have superior efficacy.

Example 2: Arguments of No Motivation and Unexpected Results During the Prosecution of U.S. Patent No. 9,308,278 [7]

The USPTO issued the ’278 patent to Agensys, Inc. on April 12, 2016, with claims to ADCs and pharmaceutical compositions comprising the ADCs. For example, independent claim 1 is as follows:

1. An antibody drug conjugate obtained by a process comprising the step of:

conjugating an antibody or antigen binding fragment thereof to monomethyl auristatin F (MMAF), which antibody or antigen binding fragment thereof is expressed by a host cell comprising a nucleic acid sequence encoding an amino acid sequence of a VH region consisting of SEQ ID NO:7, from residues 20 to 142, and a nucleic acid sequence encoding an amino acid sequence of a VL region consisting of SEQ ID NO:8, from residues 20 to 127, thereby producing the antibody drug conjugate.

On July 2, 2015, the USPTO examiner rejected the then-pending claims for obviousness over combinations of five references. According to the examiner, four of the references taught cancer immunotherapy using anti-161P2F10B antibodies such as H16-7.8 conjugated to auristatins such as monomethyl auristatin E (MMAE) for use in treating cancer, and the fifth reference taught that MMAF is an antimitotic auristatin derivative with a charged C-terminal phenylalanine residue that attenuates its cytotoxic activity compared to its uncharged counterpart, MMAE. The examiner wrote that an artisan would have been motivated to replace MMAE with MMAF based on the fifth reference’s showing of improved therapeutic effects.

In a response dated September 23, 2015, the applicant argued that the first four references would not have motivated an artisan to conjugate the H16-7.8 antibody with MMAF or to target cells expressing 161P2F10B protein with the claimed ADC because the references broadly disclosed more than twenty different monoclonal antibodies and more than fifty different cytotoxic agents, not one of which was MMAF. The applicant also argued that the claimed ADC comprising the claimed H16-7.8 antibody conjugated to MMAF produced surprising results. In support of this argument, the applicant relied on data showing that the H16-7.8 MMAF conjugate inhibited tumor growth for sixty days, a result not obtained with either the H16-1.11 MMAF conjugate or the H16-7.8 MMAE conjugate. The USPTO withdrew the obviousness rejections, and then the ’278 patent issued on April 12, 2016. The examiner wrote that the applicant’s argument of unexpected results was persuasive.

Example 3: Arguments of New Components, No Motivation, and No Reasonable Expectation of Success During the Prosecution of U.S. Patent No. 9,850,312 [8]

The USPTO issued the ’312 patent to Daiichi Sankyo Company, Limited and Sapporo Medical University on December 26, 2017, with claims to ADCs, pharmaceutical compositions comprising the ADCs, antitumor drugs and anticancer drugs containing the ADCs, and methods of treating cancer using the ADCs. For example, independent claim 1 is as follows:

1. An antibody-drug conjugate, wherein a linker and an antitumor compound represented by the following formula and anti-TROP2 antibody are connected:

-(Succinimid-3-yl-N)—CH2CH2CH2CH2CH2—C(=O)-GGFG-NH—CH2—O—CH2—C(=O)—(NH-DX) . . .

wherein the anti-TROP2 antibody comprises CDRH1 consisting of the amino acid sequence of SEQ ID NO: 23, CDRH2 consisting of the amino acid sequence of SEQ ID NO: 24 and CDRH3 consisting of the amino acid sequence of SEQ ID NO: 25 in its heavy chain variable region and CDRL1 consisting of the amino acid sequence of SEQ ID NO: 26, CDRL2 consisting of the amino acid sequence of SEQ ID NO: 27 and CDRL3 consisting of the amino acid sequence of SEQ ID NO:28 in its light chain variable region.

On October 21, 2016, the USPTO examiner rejected the then-pending claims for obviousness over three references. According to the examiner, the first reference taught drug delivery systems in which exatecan is linked to a GGFG tetrapeptide, but not the ADC with anti-TROP2 antibody and the linkers in the then-pending claims. The examiner wrote that the second reference taught ADCs using maleimidocaproyl attached to an amino acid spacer attached to a maytansinoid drug moiety, and that the third reference taught ADCs having the anti-TROP2 antibody hRS7 with a drug. The examiner wrote that it would have been obvious to prepare the ADC using the first reference’s exatecan linked to a GGFG tetrapeptide composition with the maleimidocaproyl of the second reference and the anti-TROP2 antibody of the third reference.

In a response dated January 18, 2017, the applicant amended the claims and argued that the claimed ADC comprised a novel linker having a specific structure and a novel anti-TROP2 antibody. The applicant argued that even if exatecan was known in the art, its ability to maintain and exert antitumor activity in the claimed structure was “a totally new finding” and there was no expectation of success. The applicant also argued that the only cited reference that disclosed an anti-TROP2 antibody did not disclose one with the claimed CDR sequences. The applicant argued that the references did not teach or suggest the claimed antibody or provide the necessary motivation to arrive at the claimed antibody with a reasonable expectation of success. The examiner issued a notice of allowance, and then the ’302 patent issued on December 26, 2017.

Companies developing ADCs should strategically obtain patent protection for their products, keeping in mind that their ability to have a patent granted may hinge on the success of their arguments of nonobviousness of the invention. As seen from the examples above, applicants often use a combination of arguments and claim amendments when responding to an obviousness rejection. By considering how other companies have responded to obviousness rejections by the USPTO, companies can gain insight into how to obtain and preserve patent protection for their own ADC inventions.

How to cite:
Eaton J, Miller P, Cyr SK. Four Ways to Show Nonobviousness of ADC Inventions (2018),
DOI: 10.14229/jadc.2018.10.05.001.

Original manuscript received: August 25, 2018 | Manuscript accepted for Publication: August 21, 2018 | Published online September 27, 2018 | DOI: 10.14229/jadc.2018.10.05.001.

Last Editorial Review: October 5, 2018

Featured Image: Patent Concept button. Courtesy: © Fotolia. Used with permission.

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Copyright © 2010 – 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.


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

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Gemtuzumab Ozogamicin Granted Positive Opinion for Treatment of Previously Untreated, De Novo, CD33-positive AML in Combination with Chemotherapy

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted positive opinions recommending that two Pfizer hematology medicines be granted marketing authorizations in the European Union (EU).

The first agent, gemtuzumab ozogamicin (Mylotarg™), in combination with daunorubicin and cytarabine has been granted a positive opinion for the treatment of patients age 15 years and above with previously untreated, de novo, CD33-positive acute myeloid leukemia (AML), except acute promyelocytic leukemia (APL).

The second drug, bosutinib (Bosulif®), is an oral, once-daily, tyrosine kinase inhibitor (TKI), which inhibits the Bcr-Abl kinase that promotes CML and is also an inhibitor of Src-family kinases, has been granted a positive opinion for the treatment of adults with newly diagnosed chronic phase Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML). The CHMP’s opinions for both medicines will now be reviewed separately by the European Commission (EC).

…the addition of [gemtuzumab ozogamicin] to standard chemotherapy will provide an important new treatment option for patients with acute myeloid leukemia who would typically be treated with chemotherapy alone…

Acute myeloid leukemia is a rapidly progressing, life-threatening blood and bone marrow cancer. [1] If left untreated, patients with AML will die within months, if not weeks, of their disease. AML is the most common type of acute leukemia in adults and accounts for approximately 80% of all cases of acute leukemia.[2] About 1/33,000-1/25,000 people are expected to be newly diagnosed with AML in Europe annually.[2]

Photo 1.0: gemtuzumab ozogamicin (Mylotarg™).

Chronic myelogenous leukemia (CML) is a rare blood cancer, which begins in the bone marrow, but often moves into the blood.[3] Researchers estimate that by 2020, more than 412,000 people worldwide will be diagnosed with leukemia (all types).[4] Across Europe, CML constitutes about 15% of all leukemia and occurs with an incidence of about 1-1.5/100,000.[5]

Gemtuzumab ozogamicin is an antibody-drug conjugate or ADC composed of the cytotoxic agent calicheamicin, attached to a monoclonal antibody (mAB) targeting CD33, an antigen expressed on the surface of myeloblasts in up to 90% of AML patients.[6][7][8] When gemtuzumab ozogamicin binds to the CD33 antigen on the cell surface it is absorbed into the cell and calicheamicin is released causing cell death.[7][8]

Approval process
Gemtuzumab ozogamicin was approved by the U.S. Food and Drug Administration in September 2017 for adults with newly diagnosed CD33-positive AML, and adults and children 2 years and older with relapsed or refractory CD33-positive AML.

Gemtuzumab ozogamicin was originally approved in 2000 at a higher dose under the FDA’s accelerated approval program for use as a single agent in patients with CD33-positive AML who had experienced their first relapse and were 60 years or older and who were not considered candidates for other cytotoxic chemotherapy. In 2010, Pfizer voluntarily withdrew gemtuzumab ozogamicin in the U.S. after a confirmatory trial failed to show clinical benefit and there was a higher rate of fatal toxicity compared to chemotherapy. Gemtuzumab ozogamicin has been available to individual patients through Pfizer’s compassionate use programs.

In addition, gemtuzumab ozogamicin is commercially available in Japan where it has been approved since 2005 for the treatment of patients with relapsed or refractory CD33-positive AML who are not considered candidates for other cytotoxic chemotherapy.

Gemtuzumab ozogamicin originates from a collaboration between Pfizer and Celltech, now UCB. Pfizer has sole responsibility for all manufacturing, clinical development and commercialization activities for this molecule.

Pfizer also collaborated with SFJ Pharmaceuticals Group on the registrational program for Gemtuzumab ozogamicin.

Urgent unmet medical need
“There is an urgent need to improve outcomes for leukemia patients in Europe,” explained Mace Rothenberg, M.D., chief development officer, Oncology, Pfizer Global Product Development.

“If approved, the addition of [gemtuzumab ozogamicin] to standard chemotherapy will provide an important new treatment option for patients with acute myeloid leukemia who would typically be treated with chemotherapy alone. Additionally, the potential expansion of the approved use of BOSULIF to include first-line therapy expands the treatment options for adult patients with newly diagnosed chronic myelogenous leukemia.”

The Marketing Authorization Application (MAA) for gemtuzumab ozogamicin was based on data from an investigator-led, Phase III, randomized, open-label study (ALFA-0701) in previously untreated, de novo patients.

Bosutinib currently has conditional marketing authorization in Europe related to the initial marketing authorization. The Type II Variation application for BOSULIF for adults with newly diagnosed chronic phase Ph+ CML was based on results from BFORE (Bosutinib trial in First line chrOnic myelogenous leukemia tREatment), a randomized multicenter, multinational, open-label, Phase III, head-to-head study of bosutinib 400 mg versus imatinib 400 mg, a current standard of care.

Pfizer and Avillion entered into an exclusive collaborative development agreement in 2014 to conduct the BFORE trial. Under the terms of the agreement, Avillion provided funding for the trial to generate the clinical data used to support this application and other potential regulatory filings for marketing authorization for bosutinib as first-line treatment for patients with chronic phase Ph+ CML. Pfizer retains all rights to commercialize bosutinib globally.

Last editorial review: February 24, 2018

Featured Image: Leukemia cells and scienctist testing in laboratory Courtesy: © 2010 – 2018 Fotolia. Used with Permission. Photo 1.0: gemtuzumab ozogamicin (Mylotarg™). Courtesy: © 2010 – 2018 Pfizer. Used with permission.

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Lifastuzumab Vedotin is Well-tolerated + Improves Objective Response Rate in Phase II Trial in Platinum-resistant Ovarian Cancer

Lifastuzumab vedotin, also known as DNIB0600A (RO5541081) and RG-7599, is an antibody-drug conjugate or ADC.

In clinical trials the investigational drug is compared to pegylated liposomal doxorubicin for the treatment of patients with platinum-resistant ovarian cancer.

Lifastuzumab vedotin is a humanized anti-NaPi2b monoclonal antibody conjugated to a potent anti-mitotic agent, monomethyl auristatin E or MMAE, which inhibits cell division by blocking the polymerization of tubulin. The monoclonal antibody is linked to the cytotoxic agent via a cleavable maleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl (mc-val-cit-PABC) type linker on an average of 3-4 cysteinyl (vedotin refers to MMAE + its linking structure to the antibody).

NaPi2b is expressed in ovarian cancer and other malignancies including NSCLC (Non–Small-Cell Lung Cancer) and papillary thyroid cancer.

According to the American Cancer Society, ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. On average, a woman’s risk of getting ovarian cancer during her lifetime is about 1 in 79, while the lifetime chance of dying from ovarian cancer is about 1 in 108.

ovarian cancer cells
Photo 1.0: Ovarian cancer cells.

A study by researchers from Royal Marsden NHS Foundation Trust and Institute of Cancer Research (London, United Kingdom), the Princess Margaret Hospital (Toronto, Canada), the Massachusetts General Hospital/Harvard Medical School (Boston, Massachusetts, USA) as well as Genentech/Roche and others, is the first to compare an antibody-drug-conjugate to standard-of-care in ovarian cancer patients. [1]

The results were published in the February 1, 2018 edition of Annals of Oncology.[2]

Trial design
The phase II trial included 95 patients. Forty-seven platinum-resistant patients with ovarian cancer were randomized to receive LIFA (2.4 mg/kg, intravenously, every 3 weeks [Q3W]). The remaining forty-eight patients received pegylated liposomal doxorubicin (PLD) (40 mg/m2, intravenously, Q4W). NaPi2b expression and serum CA-125 and HE4 levels were assessed.

Participating patients were followed for a median of 6.6 months.

The primary endpoint was progression-free survival (PFS) in intent to treat (ITT) and NaPi2b-high patients. The secondary outcome measures included the percentage of participating patients with an objective response according to RECIST v1.1, the duration of objective response, Overall Survival (OS), the percentage of patients with Adverse Events, and others.

Study Schematic: A Randomized Study of DNIB0600A in Comparison With Pegylated Liposomal Doxorubicin in Patients With Platinum-Resistant Ovarian Cancer (NCT01991210)

Trial results
The stratified Progression Free  Survival (PFS) hazard ratio was 0.78 (95% CI, 0.46-1.31; p=0.34) with a median PFS of 5.3 vs. 3.1 months (lifastuzumab vedotin vs. pegylated liposomal doxorubicin arm, respectively) in the intend to treat population.

In the NaPi2b-high patients this was 0.71 (95% CI, 0.40-1.26; p=0.24) with a median Progression Free  Survival of 5.3 vs. 3.4 months (lifastuzumab vedotin vs. pegylated liposomal doxorubicin arm, respectively).

The researchers reported that in the full cohort, the objective response rate or ORR to the therapy was 34% (95% CI, 22-49%, lifastuzumab vedotin) vs. 15% (95% CI, 7-28%, pegylated liposomal doxorubicin) in the intent to treat (ITT) population (p=0.03), and 36% (95% CI, 22-52%, lifastuzumab vedotin) vs.14% (95% CI, 6-27%, pegylated liposomal doxorubicin) in NaPi2b-high patients (p=0.02).

Adverse events
Toxicities included grade ≥3 adverse events. (46% lifastuzumab vedotin; 51% pegylated liposomal doxorubicin), serious AEs (30% both arms), and AEs leading to discontinuation of drug (9% lifastuzumab vedotin; 8% pegylated liposomal doxorubicin). Five (11%) lifastuzumab vedotin vs. 2 (4%) pegylated liposomal doxorubicin patients had grade ≥ 2 neuropathy.

Overall, the researchers concluded that lifastuzumab vedotin Q3W was well-tolerated and improved objective response rate with a modest, non-statistically significant improvement of Progression Free  Survival compared to pegylated liposomal doxorubicin in platinum-resistant ovarian cancer.

While the response rate for the MMAE-containing ADC was promising, the researchers noted that the response durations were relatively short.

According to the researchers, the study also highlights the importance of evaluating both response rates and duration of response since an objective response rate alone may not translate to durable responses when evaluating antibody-drug conjugates in the treatment of ovarian cancer.

Although based on earlier trial results clinical investigators expected that positive results from a previous trial could lead to a phase III trial with a high likelihood of success, Genentech/Roche has discontinued the development of lifastuzumab-vedotin.[3]

Last Editorial Review: February 12, 2018

Featured Image: Teal ribbon awareness to support Ovarian/Cervical Cancer. Courtesy: © 2010 – 2018 Fotolia. Used with Permission. Photo 1.o: Ovarian cancer. Courtesy: © 2010 – 2018 Fotolia. Used with Permission.

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University of Copenhagen’s Spin-out company ADCendo to Explore and Commercialize Novel ADC Targeting uPARAP Receptor

Earlier this year spin-out company ADCendo, the University of Copenhagen and the Capital Region of Denmark entered into a worldwide license agreement to develop novel, targeted cancer treatments against certain bone, connective tissue and brain cancers. The agreement an important step towards a possible treatment for these cancers.

ADCendo was founded in 2017 by the scientist inventors, Niels Behrendt, Lars Henning Engelholm and Christoffer Nielsen, from The University of Copenhagen and Rigshospitalet and Henrik Stage, a biotech-entrepreneur active in several biotech companies and previously CEO/CFO of Santaris Pharma which was acquired by Roche in 2014.

Focusing on antibody-drug conjugate or ADC, the agreement grants ADCendo worldwide rights to explore and commercialize  inventions made by researchers at the Finsen Laboratory, a cancer research lab at Rigshospitalet which is a part of Copenhagen University Hospital, Denmark.

The laboratory´s basic research involves many years of extensive research of the mesenchymal target receptor, uPARAP, a newly discovered member of the macrophage mannose receptor family of endocytic transmembrane glycoproteins. The receptor is highly expressed by certain mesenchymal cells that are located at sites of active tissue remodeling, including human cancer, especially on sarcoma and glioblastoma cells. At the same time, with very limited expression in healthy adult tissue. Moreover, uPARAP is a constitutively recycling endocytic receptor that efficiently delivers its cargo directly into the endosomal/lysosomal system to efficiently mediate ADC processing and intracellular drug release in cancer cells.[1]

Drug candidates
ADCendo’s drug candidates are a new class of highly potent biopharmaceutical drugs composed of an antibody linked to a biologically active drug or cytotoxic compound. This allows them to combine targeting capabilities of antibodies with the cell-killing ability of cytotoxic drugs.

In preclincal development the ADCendo scientists utilized a specific monoclonal antibody targeting uPARAP, to develop a uPARAP-directed antibody-drug conjugate coupled to the highly toxic dolastatin derivative, monomethyl auristatin E, via a cathepsin-labile valine-citrulline linker. [2]

“By targeting antigens that are highly expressed in certain cancer tissues and that hold strong ability of being internalized into the cancer cell, we can actively aim for and attack the cancer. This leaves the healthy cells much less affected than treatment with traditional chemotherapy drugs,” noted Henrik Stage, CEO of ADCendo.

Published research
Published research has documented ADCendo drug candidates’ ability to completely eradicate human cancers in animal models.

“We are excited about the opportunity to further research, develop and commercialize these drug candidates for treatment of some very serious bone, connective tissue and brain cancers for which today there are no treatments available. We will now select the most promising ADC drug candidate and take it through preclinical and clinical development and hope it may end up as a new treatment option with the potential to significantly impact the lives of cancer patients,” Stage explained.

Under the terms of the license agreement, the University of Copenhagen and Capital Region of Denmark are eligible to receive milestone payments upon successful achievement of key development – and registration milestones as well as royalties. Niels Skjærbæk, Senior Executive Advisor at the Tech Transfer Office at University of Copenhagen helped facilitate the licensing agreement.

“A promising spin-out biotech company is always a significant achievement. The ADCendo founders have been very focused and displayed great determination through this process, we are therefore all very excited about this new cancer biotech company, and we will follow the drug development challenges with great interest,” Skjærbæk added.

A number of activities aimed at investigating the use and commercialization of the ADC drugs targeting the uPARAP receptor in cancers are partly funded by a pre-seed grant from Novo Seeds. Christina Trojel-Hansen, Senior Investment Associate of Novo Seeds comments:

“We are pleased to see the significant progress the scientific founder team has made towards the building a start-up company with the support from the pre-seed funding program. ADCendo’s technology is based on exiting new biological insight and could potentially be developed for severe cancers with a high unmet medical needs,” Trojel-Hansen concluded.

ADCendo has secured funding for its early preclinical activities related to lead compound selection, pharmacology and preliminary tox studies and will initiate discussions with potential investors regarding the funding needed for scaling up, IND enabling tox and preparation for and making phase I/II studies.

Last Editorial Review: November 4, 2017

Featured Image: Nyhavn, Copenhagen, Denmark. Courtesy: © 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.


Annual World ADC Awards 2017: And the Winner is…

Earlier this month, the 8th World ADC meeting, held September 20 – 22, 2017 in San Diego and organized by Hanson Wade, offered a detailed presentation across multiple-streams of learning, covering every element of antibody-drug conjugates development – from early discovery, development, manufacturing and clinical programs.

Experts in the field shared information on identifying novel tumor associated antigens, effectively translating into the clinic and ensuring readiness for commercial scale manufacturing of antibody-drug conjugates. One of the exciting – and festive – programs was the announcement of the winners of the the 2017 Annual World ADC Awards.

Innovation, leadership and devotion
Now in it’s 4th year, the Annual World ADC Awards held during the 8th World ADC, showcased innovation, leadership and devotion by a select number of companies, teams and individuals in the industry.

The Awards, across 9 categories recognizes the extraordinary endeavors, teamwork and commercial acumen that has propelled the field of antibody-drug development to the forefront of cancer research and beyond

This year, the awards ceremony, sponsored by AbbVie, Immunogen, Ambrx, and Medimmune, took place on September 21 at the Sheraton San Diego Marina. The Awardees were shortlisted from  over 1600 votes cast and scientific proposals from each submission  were evaluated by our Judging panel.

“Every year the judges are impressed with the level of innovation and scientific breakthroughs that these companies are driving. This year is no exception and we are delighted to see the calibre and quantity of entries – showing the growing momentum and advances being made within the industry,” noted Fiona Mistri, World ADC San Diego’s Program Director.

“The World ADC Awards showcase excellence within the antibody-drug conjugate-field. This year’s winners represent once again the dedication, leadership and innovation that exists in this crucial area of oncology therapeutics,”  said Jagath Reddy Junutula, Ph.D, Vice President of Research & Development at Cellerent Therapeutics and judge of the Awards.

Junutula is a recognized expert in antibody-drug conjugate development and most recently spent over 10 years at Genentech, where he led cross-functional R&D teams in both ADC and bi-specific antibody-based cancer immunotherapeutic programs in the Discovery Oncology, Research and Early Development Division.

“These Awards shine a spotlight on these companies leading the field and as a judge once again I was delighted to see the growing momentum and progress within the field,” Junutula added.

Best Contract Manufacturing (CMO) Provider
This year, Lonza won in the category Best Contract Manufacturing Provider. Celebrating 10 years of milestones in the manufacturing of antibody-drug conjugates, intermediates, drug substance process development and manufacturing, the company has been working with many clients to deliver innovative lifesaving targeted therapies in the form of antibody-drug conjugates to oncology patients worldwide.

Lonza’s clear dedication to the antibody-drug conjugates promise of reduced systemic toxicity and improved clinical outcome has shaped the company’s investments and strategy, which, according to Lonza, will continue to evolve to help drug innovators deliver on the promise of more effective therapeutics to meet the unmet medical needs of (cancer) needs.

Most Promising Clinical Candidate
In the category ‘Most Promising Clinical Candidate‘ ImmunoGen won this year with their investigational agent mirvetuximab soravtansine, also known was IMGN853. The novel antibody-drug conjugate specifically targets folate receptor alpha (FRα)-expressing cancer cells and kills them with an anticancer agent known as the maytansinoid DM4.

Data from a pooled analyses of three Phase I expansion cohorts, as well as from a Phase Ib/II clinical study known as FORWARD II (NCT02606305) has shown encouraging activity in platinum-resistant ovarian cancer. In a subset including 36 patients meeting inclusion criteria, including platinum-resistant disease and medium or high levels of FRα, who had received prior therapy showed a response rate of 47% and a median progression-free survival of 6.7 months.

Best New Drug Developer
Mersana Therapeutics won in the category ‘Best New Drug Developer.’ The clinical-stage biotechnology company develops novel antibody-drug conjugates with a with highly differentiated and proprietary development platforms that allow for significantly higher drug loads, with the potential to provide greater efficacy while simultaneously increasing tolerability.  The company’s lead product candidate, XMT1522, is in Phase I clinical trials. A second product candidate, XMT1536, is expected to be entering clinical trials in early 2018.

In 2016 the Mersana received an award of ‘Best ADC Platform Technology’ for the company’s Dolaflexin® technology. The awards recognized the company, the company’s scientific leadership and innovation within antibody-drug conjugate research.

4th World ADC Awards (2017) Winner Runner-up
Best Platform Technology Bicycle Therapeutics SynAffix
Most Promising Clinical Candidate ImmunoGen (Mirvetuximab soravtansine) Stemcentrx
Best CMO Provider Lonza BSP Pharmaceuticals
Best New Drug Developer Mersana Heidelberg Pharma
Best CRO Provider PPD SynGene
Best Publication 2016 A Biparatopic HER2-Targeting Antibody-Drug Conjugate Induces Tumor Regression in Primary Models Refractory to or Ineligible for HER2-Targeted Therapy.Li JY, Perry SR, Muniz-Medina V, Wang X, Wetzel LK, Rebelatto MC, Hinrichs MJ, et al.Cancer Cell. 2016 Jan 11;29(1):117-29. doi: 10.1016/j.ccell.2015.12.008. Targeted drug delivery through the traceless release of tertiary and heteroaryl amines from antibody-drug conjugates.Staben LR, Koenig SG, Lehar SM, Vandlen R, Zhang D, Chuh J, Yu SF, et al.Nat Chem. 2016 Dec;8(12):1112-1119. doi: 10.1038/nchem.2635.
Individual Input to the Field 2016 Gregory Winter
Long Standing Contribution Jagath Reddy Junutula

Last Editorial Review: September 22, 2017

Featured Image: Banquet Hall | World ADC Awards 2017. Courtesy: © 2017. Hanson Wade. 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.


Registration of Antibody Drug Conjugates

Antibody Drug Conjugates (ADC) are a rapidly expanding area of pharma company pipelines. They combine the targeting of an antibody with the potency of a small molecule. Such a simple and elegant approach has far reaching consequences for the IT infrastructures that were established and implemented for antibody and small molecule drug discovery. The ability to track data associated with ADCs is critical for projects to conduct structure-activity relationships (SAR) and ultimately be successful. Herein we describe a simple approach to assigning a unique ID number to ADCs that involves only minimal modification to the established registration processes for the separate antibody and small molecules components.

1.0 Introduction
Antibody drug conjugates represent an increasingly important area for drug discovery.[1] They combine the best components of both antibodies and drugs.[2] The antibody provides the selective targeting of the therapeutic while the highly potent drug drives a high efficacious response.[3]

In addition to the many challenging discovery and development complexities presented by these hybrid biologic-small molecule entities, data management also needs to be addressed. While drug discovery has implemented effective software solutions for registration of the individual components of an ADC (i.e. antibody, drug), the ability to describe and register the combined (ADC) product presents interesting challenges for current IT infrastructures, particularly in instances where the existing component registration workflows do not accommodate each other and may additionally have evolved in completely distinct software environments.

The ability to track data associated with ADCs is critical for projects to conduct structure-activity relationships (SAR) and ultimately be successful. While a covalent bond elegantly joins the worlds of antibody and small molecule, the marriage of these two domains in the cheminformatics arena represents a significant undertaking.

Figure 1.0: (a) Linker-Drug MC-Val-Cit-PABC-MMD, a lysosomally cleavable dipeptide linker that releases monomethyl dolastatin 10 (MMD); (b) Linker-Drug MC-MMD, a non-cleavable linker that releases Cys-MC MMD in the lysozyme. (Click to enlarge Figure).

2.0 Registration of small molecules
Registration is the process of assigning corporate identifiers to unique entities for the purpose of tracking them through discovery pipelines. For small molecules, registration is routine. Card systems were originally used, but the process has since been computerized. Small molecules are registered after their chemical structures have been determined; this requirement essentially provides that for a corporate ID to be assigned to a structure the corresponding compound must have been made.

Each structurally unique molecular entity is assigned its own corporate ID. Additionally each batch, or lot, of compound material is assigned a unique lot number.

The relationship between the physical material and a lot number is always immutable. Almost always the registration system enforces a rule that the relationship between a structure and its corporate ID, once assigned, is also immutable. Since the structure must be determined prior to registration the need for changes are rare. When changes do occur, they result in the lot(s) being assigned a different corporate ID.

The registration system will normally allow for the registration of materials of unknown structure, usually by requiring that such materials be assigned a unique name, but also by allowing a special character (e.g. ‘X’) to represent an unknown component of an otherwise determined structure. The virtual registration of compounds without physical lots can also be permitted, but in these cases a different class of identifiers may be assigned.

Culturally, registration is ingrained into the thinking of chemists. In the past, productivity was sometimes assessed by the number of compounds registered. Since pharmacologically active compounds in discovery rarely have trivial names, the corporate ID serves as a substitute, being used in publications, patent applications, internal documents and presentations.

3.0 Registration of biologics
For biologics, the process of registration has been defined much more recently. For developers, the first instinct was to mirror the behavior of small molecule registration systems. This was challenging for a number of reasons.

Biological macromolecules are large and an absolute representation of their chemical structure is intractable. For proteins, the amino-acid sequence can be used as a surrogate for structure. However biological proteins, especially those that are secreted from the cell, are not simply polypeptides. Many proteins are post-translationally modified (e.g. by glycosylation). In most cases, the absolute structure of the glycans and their points of attachment will not be known, and a batch of protein may well be heterogeneous in respect of its post-translational modifications.

Usual practice in biologics registration is to use the amino acid sequence as the uniqueness-determining representation of the chemical structure. Variations in glycosylation may very well occur between lots of material. Exceptions can be made if scientists intend to make a purified form of post-translationally modified protein that differs substantially from the bulk form; such proteins can be assigned unique corporate IDs.

The registration of biologics is procedurally different in that the structure of the registered material is not always independently determined (the sequence of the protein is derived from the encoding plasmid and rarely verified by mass spectroscopy prior to registration). In many cases, the sequence of the protein will not be determined at all before a corporate ID is needed to track assay results (e.g. an antibody derived from a hybridoma). In these cases, the unique identifying information is essentially the process by which the biologic was produced (e.g. isolated from that hybridoma cell line) rather than an explicitly determined state. A consequence of this is that changes in the identifying information for a protein are much more common than for small molecules.

There are two approaches to addressing this challenge. One is to maintain the rule for small molecules that the relationship between identifying information and corporate ID is immutable once assigned. Such a system must endure the inconvenience of tube re-labelling and record modification should lots of material require a change of corporate ID.

The alternative approach is to conserve the relationship between a batch of material and its corporate ID whenever possible. In this approach the identifying information for a corporate ID can be changed provided no lots exist for which the old information remains correct. A consequence of this approach is that 2 corporate IDs can become synonymous if one is modified to have the same identifying information as another, and in this case the entities merge and retain a single preferred corporate ID.

Although the second approach may seem more reasonable for biologics, situations where a corporate ID can be assigned to a material by both state and process are very complex, and for this reason we at Abbvie have moved from the second approach to the first.

Registration is a more recent practice for biologics and the metadata that needs to be collected for each registered material is more complex than for small molecules. Consequently, processes must be designed to keep data entry as simple as possible and to ensure that it is carried out by the person most likely to know the required information. Biologists typically are less comfortable using numeric identifiers as substitutes for trivial names. They often rather prefer information-rich names (e.g. Mouse anti-Human KDR [IgG1/kappa]). We enforce uniqueness of these names, so that each corporate ID maps to a single name, but also allow a more free text lot name where variations between lots of the same material can be captured. However, lot consistency is important in any discovery endeavor and this should be an exception.

4.0 Registration of ADCs
Since ADCs comprise a small molecule component and a biologics component, information about them already resides in both the small molecule and biologics registration systems. The small molecule component itself comprises a payload (the active small molecule drug) and a linker (used to connect the drug to the protein). The payload, the linker and a reagent in which the payload and linker are attached all exist as chemical reagents and can therefore be registered. In practice, the linker, as a commercial off the shelf reagent that is not independently tested, is rarely registered. Uncertainties about the molecular nature of each of the components reside in their own systems.

For example, if we do not know the sequence of an antibody that is to be conjugated, then its corporate ID in the biologics registration system will be definite, but assigned by process. Similarly, if we do not know the structure of the combined payload/linker, perhaps because it is proprietary to a collaborator, then the small molecule corporate ID will be definite, but assigned on the basis of a unique name.

Figure 2.0: X-combo is a virtual compound with X representing the antibody to which the Linker-Drug is conjugated that enables GBRS to determine if an ADC is unique. (Click to enlarge Figure).

At Abbvie, two Accelrys products are used for registration. The Global Biologic Registration System (GBRS) is used to register antibodies. This uses the amino acid sequence to determine whether or not an antibody is unique and assigns both a PR# as its corporate ID (for PRotein), for example, PR-123456 and an individual lot#.

For small molecule registration, the software A-coder is used. This determines uniqueness based on chemical structure and assigns both an A# as the corporate ID (i.e. , A-1307119.0 where the .0 signifies it is the free base) and an individual lot#.

The same number sequence is used by both software packages removing the possibility of identical PR- and A-numbers.

When research into ADCs was initiated at Abbvie, it was recognized immediately that to ensure data integrity a registration process would need to be implemented. Unfortunately, neither GBRS nor A-coder had the required functionality to perform registration of ADCs alone. GBRS was not chemically intelligent and thus unable to determine uniqueness of the ADC. A-coder was only designed for small molecules and was not able to handle the large amino acid sequences of the antibody.

To minimize the impact on already established workflows for both antibodies and small molecules, a solution that leveraged both GBRS and A-coder was desired.

The first decision was that ADCs would be assigned a DC# (for Drug-Conjugate) as its corporate ID. This decision was taken so that as soon as a scientist saw data associated with the moniker A- (small molecule), PR- (protein) or DC- (ADC) the type of molecule would be immediately apparent.

Next, the decision of whether GBRS or A-coder would be used to register ADCs was addressed. Recognizing that the inventory management of ADCs was more similar to inventory management for biologics than to that for small molecules, GBRS was selected. GBRS was also selected as it enabled more sophisticated metadata capture for biologic entities and was the newer of the two registrations platforms at Abbvie.

As GBRS did not possess the chemical intelligence to determine the uniqueness of an ADC, a mechanism that enabled this was required. The solution was to use the combination of the PR# from the antibody and the A# from the linker-drug to define a unique ADC in the name field of GBRS.

For the example in Figure 2.0 “ADC-123456-1307119” would be entered in the name field of GBRS. As both the antibody and linker-drug identifiers would be generated by their respective registration systems designed to handle the appropriate entities, all of AbbVie’s registration rules would be applied appropriately.

While in principle this would provide a way to determine uniqueness of an ADC, there was a catch. Unfortunately, during conjugation the linker-drug structure is chemically modified which leaves the possibility for two unique linker-drugs to give rise to equivalent ADCs. For example, as shown in Figure 2, Linker-drug A contains a bromine, while Linker-drug B has an iodine resulting in a unique A# for each compound. During conjugation, the halogen is displaced by the antibody with both linker-drugs affording the same ADC. However, by this method of annotation GBRS would perceive that the two reactions produced different ADCs, as the two combinations of PR# from the antibody and A# from the linker-drug are unique.

This complication was resolved by introduction of a virtual compound called the “X-combo”. This virtual compound has an X representing the antibody and the chemical structure of the linker-drug after conjugation to the antibody (Figure 2.0). During registration, this enables A-coder to determine whether the X-combo is unique and to generate a corresponding A#. In GBRS, the combination of antibody PR# and X-combo A# in the name field can then be used to determine if this is a unique ADC or one that has already been registered and assign the correct DC#.

Figure 3.0: Step 1 of association process: structure of retrieval the linker-drug. (Click to enlarge Figure)

GBRS creates an ADC registration event when the scientist provides both an antibody and X-combo corporate ID. GBRS assigns a DC corporate ID based upon three pieces of information: 1) antibody corporate ID (PR-#), 2) small molecule X-Combo (A#), 3) drug-to-antibody ratio (DAR). A DAR2 and DAR4 molecule of the same antibody and X-combo will be assigned 2 different DC corporate ID’s. If an already existing antibody and X-combo have been registered this will become a new batch of material.

In order to facilitate SAR on the ADC and its individual components (antibody, linker, drug), the appropriate A#, PR# and DC# for an ADC had to be associated together. To aid in this association, the ADC Component Association Tool was developed to enable this in collaboration with Discngine. The ADC component is achieved in a simple 5 step procedure.

First, the structure of the linker-drug is retrieved using the A# (Figure 3.0). Next, the drug is identified either by modification of the retrieved linker-drug structure or using the A#.

The mechanism of action of the drug is also selected from a drop-down list at this stage. If the mechanism of action of the drug has not previously been registered, a new mechanism of action term can be entered manually and it is then captured in the drop-down list (Figure 4.0).

Figure 4.0: Step 2 of association process: identification of the payload.(Click to enlarge Figure)

As the structure of both the linker-drug and drug are known, the linker is then automatically identified by the software (Figure 5).

The ADC Association Tool identifies the linker structure from the Combo molecule based upon what chemical structure was identified as the drug during the previous step and removing this from the Combo chemical structure leaving the linker chemical structure.

The shorthand name for the linker is selected from a drop down list, for example, MC-Val-Cit-PABC. If the linker has not previously been registered, a new linker term can be entered manually and it is then captured in the drop-down list. Then the type of linker, for example, dipeptide or non-cleavable, is also captured. For linker-drugs with a non-cleavable linker, the free drug is not likely to exist. As a result, for these linker-drugs, the cysteinylated analogue is registered to represent the active species that is released from the lysosome (Figure 5.0).

Figure 5.0: Step 3 of association process: automatic identification of linker. (Click to enlarge Figure)

The final step is exemplification of the X-combo structure. The software retrieves the structure of the linker-drug, which can then be modified to represent the chemical structure of the linker-drug after conjugation to the antibody, with X representing the antibody (Figure 6.0).

Finally, the ADC Component Association Tool registers the X-combo in A-coder thereby conforming to AbbVie’s registration process rules on structure. The association between the ADC components along with the additional criteria on MOA and linker are stored in a custom ORACLE database. The element table in the A-coder registration system was modified to allow the X-combo molecules to contain the element X, which represents the antibody. The ADC Association Tool sends all of the metadata required for the X-combo molecule registration and assignment of its corporate ID.

Figure 6.0: Step 4 of association process: exemplification of X-combo structure.Having identified the 4 components of the ADC in the final step of the association process, a summary of the data from steps 1 to 4 is provided for the user to check (and edit if necessary) prior to registration. (Click to enlarge Figure)

Having created an association between all the components of an ADC, it is now possible to data mine on any aspect of an ADC. For example, one can easily search for all the ADCs with non-cleavable linkers that contain drug A-1581855. To enable substructure searching of ADCs, the structure of the X-combo was associated with the DC# of the ADC on the chemistry cartridge.

Figure 7.0 shows an example of ADCs with an MOA of auristatin. Due to the complexity and size of the structure of X-combos and linker-drugs, their visualization is not optimal. The use of metadata fields like linker, type and MOA can therefore be used to identify the structural variations within a set of ADCs being visualized.

Having associated all the components of an ADC facilitates comprehensive evaluation of SAR. All in vitro, in vivo and PK data can be uploaded to the corporate database and associated, at the lot level, with the relevant ADC component. Then, for example, it is possible to correlate the cell efficacy of the ADC with that of the free drug or the naked antibody.

5.0 Maleimide Hydrolysis
A known liability of ADCs using Cys-maleimide conjugation is the loss of the linker-drug through a reverse Michael reaction. Scientists at Genentech [4] published data showing 2 important facts:

  1. hydrolysis of the maleimide ring affords a stable attachment;
  2. the environment surrounding the cysteine influences hydrolysis of the maleimide ring.

They showed that sites with a positively charged environment promoted hydrolysis of the maleimide ring. Seattle Genetics [5] published data on maleimide hydrolysis showing that both a basic moiety proximal to the maleimide and also a short alkyl chain between the maleimide and amide can catalyze ring hydrolysis at basic pH. Pfizer [6] have nicely shown that a PEG spacer between the maleimide and amide enables base catalyzed ring hydrolysis.

Figure 7.0: Association of ADC components enables SAR visualization, for example, ADCs with auristatin as the MOA. (Click to enlarge Figure)

Maleimide ring hydrolysis is also achieved for linker-drugs with an ethyl spacer between the maleimide and valine by treatment at pH 9 for 3 days. The ring hydrolyzed maleimide structure is captured during registration of the X-combo (Figure 8.0).

Hydrolysis of the maleimide ring after conjugation can afford two possible hydrolyzed products. For clarity when visualizing the ADC structure only a single product with the X positioned alpha to the amide from the maleimide ring (as depicted in Figure 8.0) is captured in the database.

6.0 DAR Homogeneity
Having initially defined the criteria to determine a unique ADC as the combination of PR-# (antibody) + A-# (X-combo), it was decided that DAR should also be included. To enable data mining of this information, a minor modification to GBRS was made which added separate fields for aggregation, DAR and DAR separation.

Figure 8.0: X-combo is registered as the ring hydrolyzed maleimide structure (X represents the antibody). (Click to enlarge Figure)

ADCs produced by conjugation to inter-chain cysteines results in a heterogeneous DAR population. To improve both quality and consistency of ADCs synthesized at AbbVie, routine separation of the DAR species by hydrophobic interaction chromatography (HIC) was implemented. To enable immediate recognition of whether an ADC was a heterogeneous or DAR separated population, a simple terminology was adopted. For a heterogeneous DAR population the DAR was reported to one decimal place, for example, DAR 3.6. For a specific DAR peak following separation by HIC the DAR was reported as a whole number, for example, DAR 4.

7.0 Site of Conjugation
The final consideration was how to register ADCs when the site of conjugation is known, for example, with cysteine deletion and/or addition mutants. In these cases, the site of conjugation is captured in the antibody structure during the registration process for the antibody. As this is a novel antibody, it receives a different PR# to the native antibody so GBRS will recognize this and determine that the ADC is unique.

Figure 9.0: DAR Nomenclature: a) heterogeneous DAR designated by use of the decimal place, DAR 3.6; b) purified DAR designated by use of whole number, DAR 4. (Click to enlarge Figure)

To make this mutation more readily apparent, the mutated amino acid along with its location is captured in the name field during registration in GBRS. For example “ADC-123456-1307119-CYS237” would be entered in the name field to designate conjugation at CYS237. Using this format for entries in the name field not only ensures the correct identification of this ADC by the registration system, it also provides immediate clarity of the amino acid mutation(s).

8.0 Summary
A custom and novel ADC registration process has been implemented with minimal modification to AbbVie’s small or large molecule registration systems software or compound workflow. This new process enables in-depth SAR interrogation based on all components of the ADC, including the ability to perform searches based on the structure of the linker-drug. A simple terminology was implemented to discriminate between heterogeneous and separated DAR populations as well as other ADC property metadata.

ADC, antibody drug conjugate; Cit, citrulline; Cys, cysteine; DAR, drug to antibody ratio; GBRS, global biologics registration system; HIC, hydrophobic interaction chromatography; IT, information technology; MC, maleimide-caproyl; MOA, mechanism of action; MMD, monomethyl dolastatin 10; PABC, para-amino benzylic carbamate; SAR, structure-activity relationship; Val, valine.

August 14, 2017 | Authors: Adrian D. Hobson,* [a]  Jeremy C. Packer, [b] Chris C. Butler [b] and Dirk A. Bornemeier.[b]
[a] AbbVie Bioresearch Center, 381 Plantation Street, Worcester, MA 01605
[b] AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064

Corresponding Author:
* adrian.hobson@abbvie.com

Author Contributions:
The manuscript was written through contributions of all authors. / All authors have given approval to the final version of the manuscript.

Funding Sources
ADH, JCP, CCB and DAB are employees of AbbVie (or Abbott Laboratories prior to separation) and may own AbbVie/Abbott stocks or stock options and participated in the interpretation of data, review, and approval of the publication. The financial support for this work was provided by AbbVie.

We acknowledge Doug Pulsifier, Robert Gregg, Michael Huang, Sreekumar Menon, Randy Metzger, Hetal Patel, Teresa Rosenberg, Jennifer Van Camp and Philip Hajduk for their input with this project.

Original manuscript received: July 24, 2017 | Manuscript accepted for Publication: August 3,  2017 | Published online August 14, 2017 | DOI: 10.14229/jadc.2017.14.08.002

Last Editorial Review: August 11, 2017

Featured Image: Chicago, Ill.  Inner-city Complexity. Courtesy: © Fotolia. Used with permission.

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Antibody-drug Conjugates: Intracellular Trafficking of New Anticancer Therapeutics

A new article, published by a team of writers including Muhammad Kalim, Jie Chen, and Shenghao Wang from the Department of Biochemistry and Genetics, School of Medicine, College of Pharmaceutical Science, Zhejiang University, Hangzhou, People’s Republic of China, discusses the Intracellular Trafficking of New Anticancer Therapeutics.[1]

Antibody–drug conjugates or ADCs are a milestone in targeted cancer therapy that comprises of monoclonal antibodies chemically linked to cytotoxic drugs. Internalization of ADC takes place via clathrin-mediated endocytosis, caveolae-mediated endocytosis, and pinocytosis.

Conjugation strategies, endocytosis and intracellular trafficking optimization, linkers, and drugs chemistry present a great challenge for researchers to eradicate tumor cells successfully.

This inventiveness of endocytosis and intracellular trafficking has given consi­derable momentum recently to develop specific antibodies and ADCs to treat cancer cells. It is significantly advantageous to emphasize the endocytosis and intracellular trafficking pathways efficiently and to design potent engineered conjugates and biological entities to boost efficient therapies enormously for cancer treatment.

Current studies illustrate endocytosis and intracellular trafficking of ADC, protein, and linker strategies in unloading and also concisely evaluate practically applicable antibody-drug conjugates.

This article was supported by the National Nature Science Foundation of China and Special Program from the Department of Science and Technology, Zhejiang Province, People’s Republic of China.

Last editorial review: August 1, 2017

Featured Image: est tubes in clinic, pharmacy and medical research laboratory with male scientist using pipette Courtesy: © 2017. Fotolia. Used with permission.

Copyright © 2017 InPress Media Group, LLC. 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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