Over the last decade, antibody-drug conjugates (ADCs) have emerged as a highly promising new class of biopharmaceuticals. By taking advantage of the specificity of monoclonal antibodies and the potency of small-molecule chemotherapy drugs, ADCs have proven to provide a highly effective combination – particularly in the oncology space,. The recent FDA approvals of Kadcyla (Genentech), Adcetris (Seattle Genetics), Mylotarg (Wyeth Holdings / Pfizer), and Besponsa (Wyeth Holdings / Pfizer), as well as the over sixty other ADCs in clinical trials, show that these drugs represent an increasing proportion of newly approved cancer therapies and will generate growing revenues for firms innovating in the field.  Accompanying this burst in ADC development is the corresponding activity in the patent space.  This article summarizes some of the important developments.

ADC Mechanism of Action
An ADC is composed of an antibody conjugated to a cytotoxic compound (the payload) via a chemical linker. Traditional chemotherapy drugs can be highly effective at destroying cancer cells, but in general their specificity for cancer tissue is extremely low, and many healthy cells are killed as well. However linking highly potent anticancer drugs to antibodies that bind to antigens present at high levels in tumor cells greatly improves drug specificity for the cancer cells and reduces side effects. Generally, once an ADC binds an antigen on the cancer cell surface, it is internalized and sent along the endosome/lysosome pathway for degradation. In the lysosome the payload is released either through specific cleavage of the linker by lysosome enzymes or general degradation of the antibody. The released cytotoxic compound then leaves the lysosome and causes death of the cancer cell.  See the following scheme which illustrates this biochemical process.

ADC Patent Landscape
The ADC research space and development pipeline are growing rapidly.  This section is not meant as an exhaustive review of the patent landscape. Rather this section will provide insight into unique patent strategies employed for the intellectual property protection of ADC drugs. Because ADCs represent an extension of the well-established field of conventional therapeutic antibodies and a combination of biologic and organic drug components, the patent landscape is relatively crowded. However, the three components of an ADC, i.e. the antibody, the payload drug, and the linker, as well as their unique combination provide significant opportunities for innovation.

Early ADC therapies suffered from low potency relative to standard chemotherapy agents. However, developments in linker technologies and the use of cytotoxic agents that were otherwise too potent for direct administration greatly improved ADCs’ effectiveness. The first ADC therapy approved by the FDA, is marketed as Mylotarg (acquired by Pfizer via Wyeth Holdings). This drug targets the antigen CD33, which is expressed at high levels on the surface of acute myeloid leukemia cells, to deliver a highly toxic calicheamicin payload. Mylotarg had a challenging history, and despite accelerated approval in 2000, it was voluntarily removed from the market after several early deaths in follow-on confirmatory trials. After significant adjustments to the dosing regimen, Mylotarg was reapproved in 2017.  See, (US5773001)

Since Mylotarg’s first introduction to the market, three other ADC drugs have been approved by the FDA. Besponsa (US9351986B2, Wyeth Holdings) employs the same payload and linker of Mylotarg conjugated to an anti-CD22 antibody that targets B-cell precursor acute lymphoblastic leukemia cells. Both Mylotarg and Besponsa employ hydrazone linkers that are specifically cleavable in the lysosome and are otherwise highly stable in circulation. The calicheamicin payloads delivered by these drugs had also been under investigation by other groups, such as American Cyanamid Company as seen by an early patent from this area (US5714586).

Adcetris (US7829531), licensed by Seattle Genetics, targets the antigen CD30, which is present at high levels in certain non-Hodgkins lymphoma cells. Its valine-citrulline linker (US7745394) is specifically cleavable by cathepsin B, a lysosome enzyme, allowing rapid release of the payload after internalization. Citrulline, biologically generated by post-translational modification of arginine residues, has higher stability in circulation than other amino acids and improves the bioavailability of valine-citrulline-linked ADCs. Other companies such as Ambrx (US9975936) have attempted to push this approach further through the use of nonnatural amino acids with even higher stability. Adcetris delivers a highly-potent MMAE payload (US6884869). Companies such as Mersana have developed several other auristatin compounds for use as ADC payloads (US9943609).

Kadcyla (US8337856), licensed by Genentech, targets the HER2 antigen expressed at high levels in certain metastatic breast cancers and delivers the chemotherapy agent DM1. Its linker is noncleavable, but degradation of the antibody in the acidic environment of the lysosome eventually leads to payload release. The DM1 payload is typical of the relatively large class of maytansinoid cytotoxic agents, which are under development by several companies such as ImmunoGen (US5208020).

As will be discussed in greater detail in future pieces, novel approaches to ADC antibodies, linkers, and payloads have been developed, both from a technological and IP perspective. The targeting of noninternalizing antigens (US20150030536, US20170028080A1) has generated particular excitement. Additionally novel antibody formats (US9290577, US9856314), the use of masked proproteins (US20130101555), and conditionally-active antibodies (US9637734B2) have provided new targeting mechanisms.

Linker technologies also present significant opportunities for innovation. Different biological conjugation and cleavage mechanisms have been developed, such as the use of reactive thiols on engineered cysteine residues (US7521541B2), sortase-mediated conjugation (US9872923), MTGase-mediated linkage (US15214331), and transglutaminase linkage (US20170106096A1). Several other proprietary linkers have been developed as well (US9540438B2, US7223837B2).

Payload development provides further opportunities for innovation. Both previously-developed and novel cytotoxic agents have been employed as ADC payloads, such as anthracyclin derivatives (US8900589), duocarmycins (US9629924B2, US5475092, US5585499), taxanes (US7390898), benzodiazepine derivatives (US9889207B2, US8765740, US9242013B2US15724423), and tubulysins (US9801951B2).

As evidenced from this research and IP activity, ADCs provide an innovative solution to intractable cancers, and there are significant opportunities for technical innovation. It will be particularly interesting to see how companies manage the overlapping intellectual property landscape and nearing expirations of patents on naked antibodies and payloads that could be used in ADC therapies. Later in this series, we will discuss in greater depth advancements in antibody, linker, and payload technologies, as well as patent strategies for navigating the significant patent landscape.

Patent Number Inventor Assignee Title Issue or Publication
US5773001 Hamann et al Wyeth Holdings LLC Conjugates of Methyltrithio Antitumor Agents and Intermediates for their Synthesis 30-Jun-98
US9351986B2 Kunz et al Wyeth Holdings LLC Calicheamicin Derivative-Carrier Conjugates 31-May-16
US5714586A Kunstmann et al Wyeth Holdings LLC Methods for the Preparation of Monomeric Calicheamicin Derivative/Carrier Conjugates 3-Feb-98
US7829531B2 Senter et al Seattle Genetics Inc Drug Conjugates and their Use for Treating Cancer, an Autoimmune Disease or an Infectious Disease 9-Nov-10
US7745394B2 Doronina et al Seattle Genetics Inc Monomethylvaline Compounds Capable of Conjugation to Ligands 19-Jun-10
US9975936B2 Cujec et al Ambrx Inc Nucleic Acids Encoding Modified FGF-21 Polypeptides Comprising Non-Naturally Occurring Amino Acids 22-May-18
US6884869B2 Senter et al Seattle Genetics Inc Pentapeptide Compounds and Uses Related Thereto 26-Apr-05
US9943609B2 Yurkovetskiy et al Mersana Therapeutics Inc Protein-Polymer-Drug Conjugates 17-Apr-18
US8337856B2 Blattler et al ImmunoGen Inc Methods of Treatment Using anti-ERBB Antibody-Maytansinoid Conjugates 25-Dec-12
US5208020A Chari et al ImmunoGen Inc Cytotoxic Agents Comprising Maytansinoids and their Therapeutic Use 4-May-93
US20150030536A1 Neri et al Philogen SpA Antigen Associated with Lung Cancers and Lymphomas 29-Jan-15
US20170028080A1 Casi et al Philochem AG Targeted Drug Conjugates 2-Feb-17
US9290577B2 Hudson et al AVIPEP Pty Ltd Immuno-Conjugates and Methods for Producing Them 22-Mar-16
US9856314B2 Lowman et al CytomX Therapeutics LLC Activatable Antibodies Having Non-Binding Steric Moieties and Methods of Using the Same 2-Jan-18
US20130101555A1 Stagliano et al CytomX Therapeutics LLC Proproteins and Methods of Use Thereof 25-Apr-13
US9637734B2 Short et al BIOATLA LLC Mirac Proteins 2-May-17
US7521541B2 Eigenbrot et al Genentech Inc Cysteine Engineered Antibodies and Conjugates 21-Apr-09
US9872923B2 Grawunder et al Nbe Therapeutics AG Method of Producing an Immunoligand/Payload Conjugate 23-Jan-18
US15214331 Bregeon et al Innate Pharma Enzymatic Conjugation of Polypeptides 30-Aug-16
US20170106096A1 Hu et al Cspc Dophen Corp Homogenous Antibody Drug Conjugates via Enzymatic Methods 20-Apr-17
US9540438B2 Barfield et al Redwood Bioscience Inc Aldehyde-Tagged Immunoglobulin Polypeptides and Methods of Use Thereof 10-Jan-17
US7223837B2 de Groot et al Syntarga BV Elongated and Multiple Spacers in Activatable Prodrugs 29-May-07
US8900589B2 Beria et al Genentech Inc Anthracycline Derivative Conjugates, Process for their Preparation and their Use as Antitumor Compounds 2-Dec-14
US9629924B2 Beusker et al Syntarga BV Conjugates of CC-1065 Analogs and Bifunctional Linkers 25-Apr-17
US5475092A Chari et al ImmunoGen Inc Cell Binding Agent Conjugates of Analogues and Derivatives of CC-1065 12-Dec-95
US5585499A Chari et al ImmunoGen Inc Cyclopropylbenzindole-Containing Cytotoxic Drugs 17-Dec-96
US7390898B2 Baloglu et al ImmunoGen Inc Cytotoxic Agents Containing Novel Potent Taxanes and their Therapeutic Use 24-Jun-08
US9889207B2 Howard, PW MedImmune Ltd Pyrrolobenzodiazepines and Conjugates Thereof 13-Feb-18
US8765740B2 Li et al ImmunoGen Inc Cytotoxic Benzodiazepine Derivatives 1-Jul-14
US9242013B2 Howard et al MedImmune Ltd, Seattle Genetics Inc Targeted Pyrrolobenzodiazepine Conjugates 26-Jan-16
US9801951B2 Miao et al Concortis Biosystems Corp Drug-Conjugates, Conjugation Methods, and Uses Thereof 31-Oct-17

-Steve Kennedy and Anthony Sabatelli, PhD, JD

Steve Kennedy is a Ph.D. Candidate in the Chemistry Department at New York University. He specializes in biophysical characterization of protein complexes and is currently focused on the role of adaptor proteins in signaling pathways. Prior to attending NYU, Steve obtained his B.S. in Chemistry with Cum Laude honors at the University of Massachusetts – Boston, during which time he conducted bioanalytical mass spectrometry method development and lipidomics research.

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