Antibody-drug conjugates: Intellectual property considerations

Figures & data

Table 1. Characteristics of the 3 ADCs approved to date by the US Food and Drug Administration

ADC name	Antibody target	Key IP right US/EP	Target also used in conventional mAb therapy?	Linker	Linker cleavable?	Toxin	Site specific conjugation?	Drug Antibody Ratio
Gemtuzumab ozogamicin	CD33	US5773001/ EP0689845B1	no	hydrazone	yes	calicheamicin	no	Only 50% of the antibody is loaded at all (avg 4 – 6)
Trastuzumab emtansine	HER-2/neu	US8337856/ EP2283867B1	yes	SMCC (maleimide)	no	DM1 (maytansinoid)	no	0–8 (avg 3,5)
Brentuximab vedotin	CD30	US7829531/ EP2353611B1	no	maleimidocaproyl spacer, valine–citrulline linker, and PABC spacer	yes(cathepsin)	MMAE (auristatin)	no	3–5

* expired;

** product voluntarily withdrawn from the market in 2010.

Table 2. Examples of different types of naked antibody compound patents

Category	Example IP right	Assignee	Target	Claim language
Antibody claimed by its target or target epitope	EP1587837B1	Proscan RX	PSMA	An antigen comprising an immunogenic moiety or carrier and an epitope of the extracellular region of PSMA consisting of SEQ ID NO:8, wherein the N-terminal cysteine residue on SEQ ID NO:8 is optional. An isolated antibody or antigen binding fragment thereof, which binds to the antigen wherein the antibody and/or antigen binding fragment thereof also binds to PSMA.
Antibody claimed by functional properties	EP1347730B2	Seattle Genetics	CD30	An antibody that immunospecifically binds CD30 and exerts a cytostatic or cytotoxic effect on a Hodgkin's disease cell line in the absence of conjugation to a cytostatic or cytotoxic agent.
Antibody claimed by expressor cell	EP0660721B1	Dana Farber	CD22	A monoclonal antibody that: is produced by a hybridoma cell line selected from the group consisting of HB22–7 (ATCC No. HB 11347), HB22–22 (ATCC No. HB 11348) and HB22–23 (ATCC No. HB11349) […]
Antibody claimed by sequence	EP0590058B1	Genentech	HER2	A humanized Antibody which comprises a VL domain comprising the polypeptide sequence X and a VH domain comprising the polypeptide sequence Y.
Antibody claimed by sequence	EP1951757B1	Xencor	CD30	An anti-CD30 antibody, comprising a variable heavy chain sequence 1 and a variable light chain sequence 2

* expired; the symbol […] indicates that claim language has been truncated.

Table 3. Suitable patent category if target and antibody are known, but not in an ADC

Embodiment	Target	Example IP right	Assignee	Claim language
Target and antibody thereagainst are known, but not in an ADC	cKIt	US20140271688	Novartis	ADC of the formula Ab-(L-(D)n)n or a pharmaceutically acceptable salt thereof; wherein Ab is an antibody or antigen binding fragment thereof that specifically binds to an epitope of human cKIT; L is a linker; D is a drug moiety; m is an integer from 1 to 8; and n is an integer from 1 to 10.

Table 4. Patents protecting new antibody concepts that can be used in ADCs

Technology	Embodiment	Example IP right	Assignee	Claim language
New antibody format	Diabody	EP2516462B1	Avipep	An isolated protein comprising an immunoglobulin variable region comprising:(i) at least 2 cysteine residues positioned within framework region (FR) 2, wherein if at least 2 of the cysteine residues in FR2 are not conjugated to a compound then a disulfide bond is capable of forming between the cysteine residues in FR2; and/or(ii) at least 2 cysteine residues positioned within framework region (FR) 3, wherein if at least 2 of the cysteine residues in FR3 are not conjugated to a compound then a disulfide bond is capable of forming between the cysteine residues in FR3.
Conditionally active Biologics	Antibodies are activated and/or inactivated at defined physiological conditions.	US8709755	BioAtla	A method of preparing a conditionally active antibody, the method comprising the steps of:i. selecting a wild-type antibody against an antigen;ii. evolving the DNA which encodes the wild-type antibody using one or more evolutionary techniques to create mutant DNAs;iii. expressing the mutant DNAs to obtain at least one mutant antibody;iv. subjecting the at least one mutant antibody and the wild-type antibody to an assay under a normal physiological condition selected from the group consisting of temperature, pH, osmotic pressure, osmolality, oxidation and electrolyte concentration, and to an assay under an aberrant condition selected from the group consisting of temperature, pH, osmotic pressure, osmolality, oxidation and electrolyte concentration; andv. selecting the conditionally active antibody from the at least one mutant antibody […]
Cleavable masking peptides	Masking peptides are released, e.g., by proteases secreted by the tumor	US20100189651	CytomX	A modified antibody comprising: an antibody or antibody fragment (AB), capable of specifically binding its target, coupled to a masking moiety (MM), wherein the coupling of the MM reduces the ability of the AB to bind its target such that that the dissociation constant (Kd) of the AB when coupled to the MM toward the target is at least 100 times greater than the Kd of the AB when not coupled to the MM toward the target
Target which does not require toxin internalization	Extra domains A and B of fibronectin	US20150030536	Philogen	A method of treating lung cancer or lymphoma in an individual, comprising administering to the individual a therapeutically effective amount of an antibody, or antigen-binding fragment thereof, which binds Extra Domain-A (ED-A) of fibronectin comprising a VH domain and a VL domain with given CDR sequences and wherein the antibody is conjugated to a molecule that has biocidal or cytotoxic activity or is conjugated to a radioisotope.

the symbol […] indicates that claim language has been truncated.

Table 5. Early ADC linker technology patents

Technology	Example IP right	Assignee	Claim language
Maleimidocaproyl-val-cit-PAB (combination with auristatins)	US7745394	Seattle Genetics	1. A method for treating cancer comprising administering to a patient in need thereof an effective amount of an antibody-drug conjugate compound having formula Ic: Ab Aa-Ww-Yy-D)p  Ic wherein Ab is an antibody which binds to one or more tumor-associated antigens D is a drug moiety selected of Formula DE: [ ]
Maytansinoids plus SMCC linker	US5208020	ImmunoGen	A cytotoxic agent comprising one or more maytansinoids linked to a monoclonal antibody or fragment thereof via a disulfide bridge at the C-3, −14, −15, or −20 position of said maytansinoids and wherein said monoclonal antibody or fragment thereof is selective for tumor cell antigens.

* expired; the symbol […] indicates that claim language has been truncated.

Table 6. Patents protecting new approaches related to ADC linker technology

Technology	Example IP right	Assignee	Claim language
Non-natural amino acids	EP1968635B1	Ambrx	A polypeptide, or salt thereof, containing at least one compound selected from the group consisting of: wherein each Ra is independently selected from the group consisting of […]
Cysteine-engineered antibodies (THIOMAB)	US20070092940	Genentech	A cysteine engineered antibody comprising one or more free cysteine amino acids having a thiol reactivity value in the range of 0.6 to 1.0, wherein the cysteine engineered antibody is prepared by a process comprising replacing one or more amino acid residues of a parent antibody by cysteine.
SMAC (sortase- mediated antibody conjugation) with N-terminal LPTXG tag/linker	WO2014140317	NBE therapeutics	A method of producing an immunoligand/payload conjugate, which method encompasses conjugating a payload to an immunoligand by means of a sequence- specific transpeptidase, or a catalytic domain thereof.
SpaceLink Technology	EP1370298B1	Syntarga	A compound of the formula V-(W)k-(X)l-A-Z wherein: V is a specifier which is removed by an enzyme, optionally after prior binding to a receptor; (W)k-(X)l-A is an elongated self-eliminating spacer system; W and X are each a 1,(4+2n) electronic cascade spacer, being the same or different; A is either a spacer group of formula (Y)m, wherein Y is a 1,(4+2n) electronic cascade spacer, or a group of formula U being a cyclisation elimination spacer; Z is a therapeutic or diagnostic moiety; k and l are independently an integer from 0 (included) to 5 (included); m is an integer from 1 (included) to 5 (included); n is an integer of 0 (included) to 10 (included), andk+1>0.
Microbial transglutaminase (MTGase)	WO2014202775	Innate	A method for conjugating a hydrophobic, high molecular weight or charged organic compound to an antibody, comprising the steps of:a) providing an antibody or antibody fragment comprising an acceptor glutamine residue;b) reacting said antibody with a linking reagent comprising a primary amine and a moiety of interest (Z), wherein (Z) is a hydrophobic compound, a charged organic compound and/or organic compound having a molecular weight of at least 500, 700 or 800 g/mol, in the presence of a TGase, under conditions sufficient to obtain an antibody comprising an acceptor glutamine linked to said moiety of interest (Z), via the linking reagent […]
SMARTag	US20120183566	Redwood	An isolated aldehyde-tagged immunoglobulin (Ig) polypeptide comprising an Ig constant region amino acid sequence comprising an amino acid sequence of a sulfatase motif, wherein the sulfatase motif is positioned within or adjacent a solvent-accessible loop region of the Ig polypeptide constant region, and wherein the sulfatase motif is not at the C-terminus of the Ig polypeptide chain.
Transglutaminase + “endosome escaping non cleavable” (EENC) linkers	US provisional 62/011,534, not published yet	Dophen	Not published yet

the symbol […] indicates that claim language has been truncated.

Table 7. Patents protecting selected toxins

Technology	Example IP right	Assignee	Claim language
Auristatins (MMAE, MMAF)	US6884869	Seattle Genetics	A compound of the formula and pharmaceutically acceptable salts and solvates there of wherein […]
Maytansinoids plus SMCC linker	US5208020	ImmunoGen	A cytotoxic agent comprising one or more maytansinoids linked to a monoclonal antibody or fragment thereof via a disulfide bridge at the C-3, −14, −15, or −20 position of said maytansinoids and wherein said monoclonal antibody or fragment thereof is selective for tumor cell antigens.
New anthracyclin derivatives	US8900589	Genentech	An antibody-drug conjugate compound comprising an antibody covalently attached by a linker L and an optional spacer Z to one or more anthracycline derivative drug moieties D, the compound having the formula (D-L-(Z)m)p-Ab or a pharmaceutically acceptable salt thereof, wherein: Ab is an antibody;
			D is an anthracycline derivative selected from the structures A and B: […]
Calicheamicins	US5714586	American Cyanamid Company	A method for preparing monomeric calicheamicin derivative/carrier conjugates with higher drug loading/yield and decreased aggregation having the formula, Pr(–X–S–S–W)m wherein: Pr is a proteinaceous carrier, X is a linker that comprises a product of any reactive group that can react with a proteinaceous carrier, W is the calicheamicin radical formed by removal of the naturally occurring methyl trisulfide group […]
Duocarmycins	EP2560645A2	Syntarga	1. A compound of formula (III): wherein […] each Z is independently a compound of formula (I), (II), (I'), or (IΓ): […]
Novel taxanes	US7390898	ImmunoGen	A compound represented by formula (I): wherein […]
Pyrrolobenzodiazepine	EP2766048B1	ADC Therapeutic & Spirogen Limited	A conjugate of formula ConjB:: where CBA represents a cell binding agent.
α-amanitin	EP2436398B1	Heidelberg Pharma	A conjugate comprising a target-binding moiety linked via a linker L to an amatoxin, wherein the linker L is connected to the amatoxin via(i) the γ C-atom of amatoxin amino acid 1, particularly via an amide linkage;(ii) an oxygen atom bound to the δ C-atom of amatoxin amino acid 3, particularly via an ester linkage, an ether linkage or a urethane linkage; or(iii) the 6′ C-atom of amatoxin amino acid 4, particularly via an oxygen atom bound to the 6′ C-atom of amatoxin amino acid 4; in each case wherein the linker L is connected to the target-binding moiety via a urea moiety.
CC-1065 (duocarmycin)	US5475092 US5585499	ImmunoGen	A cytotoxic agent comprising a cell binding agent linked via a disulfide bond to one or more analogs or derivatives of a cyclopropylbenzindole-containing cytotoxic drug, wherein said cell binding agent is a monoclonal antibody or an antigen-binding fragment of a monoclonal antibody having at least one binding site thereof, and wherein prior to linking said analogs or derivatives to said cell binding agent said analogs or derivatives are selected from the group consisting of analogs or derivatives formed from an A subunit of the formulae (A-3) or (A-4) and a B-C subunit of the formulae (F-3), (F-4), (F-5) or (F-6), said B-C subunit having a B moiety shown on the left-hand side of the formulae and a C moiety shown on the right-hand side of the formulae and wherein said A subunit is covalently linked to said B-C subunit via an amide bond from the secondary amino group of the pyrrole moiety of the A subunit to the C-2 carboxyl group of the B moiety of the B-C subunit, wherein the formulae (A-3) and (A-4) are as follows […] wherein the formulae (F-3) to (F-6) are as follows: […]
De-immunized bouganin protein toxin	US8716234	Merck	A method of inhibiting or destroying a lymphoma cancer cell comprising administering a cytotoxin to an animal having lymphoma, wherein said cytotoxin comprises a targeting moiety that binds to the lymphoma cancer cell and is linked to a modified bouganin protein, wherein said modified bouganin protein comprises AA sequence SEQ ID NO: 11, […]
Tubulysins	US2015141646	Concortis	1. A compound having the structure of Formula I: or a pharmaceutically acceptable salt thereof, wherein: A is a tubulin binding moiety; B is a functional moiety; […]
Benzodiazepine derivatives	US8765740	ImmunoGen	1. A compound represented by the following formula: or a pharmaceutically acceptable salt thereof, wherein: the double line – between N and C represents a single bond or a double bond, […]
Pyrrolobenzodiazepine	US2013028919	Seattle/Spirogen	A Conjugate having formula L-(LU-D)p or a pharmaceutically acceptable salt or solvate thereof; wherein L is a Ligand unit, LU is a Linker unit, p is 1 to 20; and D is a Drug unit comprising a PBD dimer having the following formula II wherein: R2 is 2'X […]
Pyrrolobenzodiazepines	US20110256157	Spirogen	A conjugate of formula (A) and salts and solvates thereof, wherein: the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3; […] or the compound is a dimer with each monomer being of formula (A), or with one monomer being of formula (A) and the other being of formula (B): wherein […]

* expired; the symbol […] indicates that claim language has been truncated.

Table 8. Claim categories for different types of toxin inventions

Subject matter	Claim category	Claim language
New class of toxin	Compound protection	Compound according to the general structural formula X, with R1 – Rx being [.]
Class is known, but specific toxin is novel	Compound protection	Compound of class X, having the following structural formula Y
Class or specific toxin is known, but transfer to ADC is novel	(i) Use/process protection or (ii) purpose bound compound protection	(i) Use of toxin x for the manufacture of an ADC(ii) Toxin x for use in an ADC for the treatment of cancer

the symbol […] indicates that claim language has been truncated.

Table 9. Claim categories for higher generation antibody patents

Category	Example IP rights	Assignee	Target	Claim language
2nd medical use	EP1734996B1	University of California	α vbeta 5 integrin	Use of an antibody that specifically binds to α vbeta 5 integrin, wherein the antibody is a humanized form of the antibody produced by the hybridoma deposited as ATCC Deposit No. PTA-5817, for the manufacture of a medicament for treating pulmonary edema.
Dosage patent	EP1210115B1	Genentech	HER2	Use of the anti-ErbB2 antibody huMab 4D5 for treating a human patient diagnosed with a breast cancer characterized by overexpression of ErbB2, said method comprising the steps of administering to the patient an initial dose of 8mg/kg of the anti-ErbB2 antibody; and administering to the patient a plurality of subsequent doses of the antibody in an amount that is 6 mg/kg, wherein the doses are separated in time from each other by 3 weeks.
Formulation	EP2459167B1	Roche	HER2	A highly concentrated, stable pharmaceutical formulation of a pharmaceutically active anti-HER2 antibody for subcutaneous injection comprising:a. about 50 to 350 mg/ml anti-HER2 antibody;b. about 1 to 100 mM of a buffering agent providing a pH of 5.5 ± 2.0;c. about 1 to 500 mM of a stabilizer or a mixture of 2 or more stabilizers;d. about 0.01 to 0.08 % of a nonionic surfactant; ande. more than 150 to about 16′000 U/ml, about 2′000 U/ml, or about 12′000 U/ml, respectively of a hyaluronidase enzyme.

* EP Patent revoked in opposition, appeal pending. In UK finally revoked.

Table 10. Higher generation ADC patents

Category	Example IP rights	Assignee	Target	Claim language
2^nd medical use	US20110165155	Genentech	HER2	A method for the treatment of metastatic or unresectable locally advanced HER2 positive cancer in a patient comprising administering a therapeutically effective amount of trastuzumab-MCC-DM1 wherein the patient has been previously treated with at least 2 anti-HER2 agents.
Formulation	WO2014143765	Abbvie	EGFR	A formulation comprising an anti-Epidermal Growth Factor Receptor (EGFR) antibody drug conjugate (ADC), a sugar, histidine, and a surfactant, wherein said formulation has a pH of about 5 - 7, and wherein said anti-EGFR ADC comprises an anti-EGFR antibody, or antigen-binding portion thereof, conjugated to an auristatin.

Table 11. Examples of patents claiming specific antibody/toxin combinations

Category	Example IP right	Assignee	Claim language
Combination of target and toxin class	US8337856	ImmunoGen	An immunoconjugate comprising an anti-ErbB2 antibody conjugated to a maytansinoid, wherein the antibody is huMAb4D5–8
Combination of specific antibody and toxin	US8153768	Wyeth Holdings Corporation	A composition comprising a drug conjugate, wherein said drug conjugate comprises calicheamicin derivatives and an anti-CD22 antibody and has the formula: [b]wherein the antibody comprises SEQ ID NO. […]

the symbol […] indicates that claim language has been truncated.

Table 12. European patents protecting gemtuzumab ozogamicin, ado-trastuzumab emtansine and brentuximab vedotin

EP Patent	Claimed subject matter	Closest prior art	Why inventive?
EP0689845B1	ADC with calicheamicin and hydrazine linker	EP0392384 discloses Calicheamicin succinimidyl derivatives conjugated to an antibody	Examiner accepted that “nothing in the prior art suggests that the use of the current linker system to bind calicheamicin to an antibody would yield conjugates having high immunoaffinity to the target, low toxicity and high antitumour activity.” (EP office action of May 11, 2001)
EP2283867B1	Trastuzumab maytansinoid conjugate for treatment of cancer over-expressing ErbB2	WO0069460 discloses trastuzumab, plus generally mentions combination therof with maytansine	Examiner accepted applicant's arguments of Nov 18, 2013, that (i) the specific selection of trastuzumab and maytansine would be novel over WO'460. In support of inventive step, applicant argued (ii) against Chari et al (1992), which discloses a murine anti-cancer ADC comprising a maytansinoid and an anti ErbB2 antibody as not being the closest prior art, and (ii) that it was surprising that trastuzumab retained its cytostatic activity in an ADC, and would not be degraded to a mere targeting device, thus leading to an ADC where the antibody and the toxin act in concert. Applicant had also argued that at the priority date, there was uncertainty regarding the therapeutic potential of immunoconjugates.
EP2353611B1	ADC with Pentapeptide linker plus auristatin	WO02088172 discloses pentapeptide linkers, and ADCs using them, but not auristatin	WO0208817 was the only prior art document, but although pre-filed, published after the priority date, and did thus not affect inventive step

* expired

Table 13. Abstract of the 2 EPO Appeal decisions that relate to ADC patents

Decision	Date	Patent/ application	Claimed subject matter	Outcome
T 0619/01	August 2004	EP0634938A1	conjugate of SMPT linked-humanized M195 antibody and 2-iminothiolane modified gelonin or recombinant gelonin for the treatment of leukemia	Claims found unallowable for insufficient disclosure, because the term “term “recombinant gelonin” was not properly defined. The only vague definition (JM105 E. coli expressing optimized gelonin”) would leave the burden of finding out how to arrive at recombinant gelonin entirely upon the skilled reader.
T 1014/01	Nov 2003	EP0439095B1	Antibody-based fusion protein comprising an Ig portion capable of directing the fusion protein to a tumor, an IL2 molecule capable of promoting lymphocyte proliferation, and a modified IgG1 hinge region with the 2 Cys residues replaced by Pro and Serine to permit greater flexibility in the fused molecule.	Claim 1 (3^rd request) was found inventive because prior art suggested that the hinge feature would avoid the reactive side groups in the AA sequence, not for increasing the flexibility. Further, prior art would contains no pointer to replace Cys with Pro, while prejudice against the use of Pro (“helix-killer”) would exist. 2^nd request, which recited, as an alternative, also a natural hinge region, was not deemed inventive.

* rejected;

** expired

Table 14. Patents that play a role in the Phigenix-Genentech dispute

Novel embodiment	Assignee	Case No	Claim language
US7575748	Genentech	IPR2014–00842	1. A method for the treatment of a tumor in a mammal, comprising the steps of (i) identifying said tumor as being characterized by overexpression of an ErbB2 receptor and as being a tumor that does not respond, or responds poorly, to treatment with an anti-ErbB antibody, and (ii) intravenously administering to the mammal a therapeutically effective amount of a conjugate of a humanized antibody huMab 4D5–8 covalently linked via a thioether linking group with a maytansinoid DM1 having the structure at a dose of between about 0.2 mg/kg and about 10 mg/kg (antibody-maytansinoid conjugate weight/body weight) and at a frequency of dosing selected from the group of dosing frequencies consisting of bolus, less than about 1 time per week, one time per week, 2 times per week, more than 2 times per week, and continuous infusion, whereby said tumor characterized by overexpression of an ErbB2 receptor and that does not respond, or responds poorly, to treatment with an anti-ErbB antibody, is treated.
US8337856	ImmunoGen	IPR2014–00676	1. An immunoconjugate comprising an anti-ErbB2 antibody conjugated to a maytansinoid, wherein the antibody is huMAb4D5–8
US8080534	Phigenix	1:14-cv-00287	1. A method for treating a breast condition in a subject, comprising administering to a breast tissue of the subject, a composition that (1) inhibits PAX2 expression or PAX2 activity, (2) expresses DEFB1 or (3) inhibits PAX2 expression or PAX2 activity and expresses DEFB1. 15. The method of claim 1, further comprising the step of: administering to the subject an effective amount of an anti-HER-2 agent. 16. The method of claim 15, wherein the anti-HER-2 agent is trastuzumab. 19. A method for treating a breast condition in a subject, comprising:(a) determining the PAX2-to-DEFB1 expression ratio in a diseased breast tissue from said subject;(b) determining the ER/PR status of said diseased breast tissue from said subject; and(c) based on the results of (a) and (b), administering to a breast tissue of said subject, a first composition that (1) inhibits PAX2 expression or PAX2 activity, (2) expresses DEFB1 or (3) inhibits PAX2 expression or PAX2 activity and expresses DEFB1.

Table 15. Details of different anti-HER2 ADCs in development

ADC name	Antibody	Linker	Toxin	Key IP right	Company	Status	Claim language
Trastuzumab emtansine	Trastuzumab	SMCC	DM1	US8337856	Genentech	Approved in US and EU	An immunoconjugate comprising an anti-ErbB2 antibody conjugated to a maytansinoid, wherein the antibody is huMAb4D5–8.
MM-302	scFv anti-HER2	PEG-DSPE	Liposome-encapsulateddoxorubicin	US2014023698	Merrimack	Phase 2/3	A method of treating a human cancer patient by administration of anthracycline - comprising anti-HER2 immunoliposomes, the method comprising determining a first dosage, such a dosage indicating a dose magnitude and frequency of dosing, for a patient diagnosed with a cancer characterized by expression of HER2 receptor, the first dosage being for a liposomal anthracycline chemotherapeutic agent that does not comprise an immunoliposome, which dosage is determined to provide to the patient a safe and effective amount of the liposomal formulation, and administering anthracycline-comprising anti-HER2 immunoliposomes, a plurality of which immunoliposomes is each bearing a plurality of anti-HER2 antibody molecules on its surface and each containing the anthracycline chemotherapeutic agent, wherein the anthracycline-comprising anti-HER2 immunoliposomes are administered to the patient at the first dosage.
SYD985	Trastuzumab	SpaceLink	Duocarmycin	EP2560645A2	Syntarga	Phase 1	A compound of formula (III): or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein […]
ARX788	Undisclosed	Undisclosed	Amberstatin AS269	US2015141624	AmbrX	Preclinical	wherein […]
Not available	Trastuzumab	Transglutaminase + EENC linker	MMAE, hybrid ADCs with different toxins	Not available	Dophen	R&D	Not available
Not available	Trastuzumab	SMAC with N-terminal LPTXG tag/linker	(i) DM1 (mertansine), (ii) maytansine, (iii) MMAE/MMAF (iv) α-amanitin (v) undisclosed new toxin, respectively	(i) – (iv) WO2014140317 (v) not disclosed	NBE Therapeutics	R&D	1. A method of producing an immunoligand/payload conjugate, which method encompasses conjugating a payload to an immunoligand by means of a sequence- specific transpeptidase, or a catalytic domain thereof. 6. The method according to any of the aforementioned claims, wherein the sequence-specific transpepeptidase is at least one selected from the group consisting of• a sortase enzyme, or one or more fragments or derivatives thereof• a split-intein, or one or more fragments or derivatives thereof
Not available	Trastuzumab	N-Hydroxysuccinimide ester	Tubulysin	Not available	VUMC Amsterdam	R&D	Not available

* Phase 1 study (NCT02512237) scheduled to start in September 2015; the symbol […] indicates that claim language has been truncated.