POST EVENT REPORT 2017 - 7TH WORLD ADC SAN DIEGO - www.worldadc-usa.com - World ADC Europe
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
www.worldadc-usa.com
7TH WORLD ADC SAN DIEGO
POST EVENT
REPORT 2017
Delivered By:
SUMMARY OF KEY FINDINGS
FROM 8TH WORLD ADC
SAN DIEGO 2017
8th World ADC was held in Over two days we were privileged to have 94
expert speakers from leading pharmaceutical
San Diego, CA on September and academic research labs. During this time
20-22, 2017. The 2017 we extensively discussed; current status of ADC
technology, development of several classes
conference continued its of DNA damaging agents, minimizing off-
target toxicity, solid-phase methods for bio-
reputation by arranging conjugation, resistible ADCs, maximizing drug
thought-provoking sessions delivery efficacy and therapeutic index of ADCs,
design of next generation ADCs and developing
across 4 main elements such ADCs outside oncology.
as discovery, development,
This report summarizes some of the
clinical, and manufacturing keyfindings of 8th World ADC San Diego.
aspects of ADCs.
The multidisciplinary aspect of ADC has made
WRITTEN AND COMPILED BY
huge impact on this conference uniting 650+
attendees from 220 organizations providing Manish S. Hudlikar, Ph.D.
most valuable learning and networking
opportunity of 2017.
“OVER TWO DAYS WE WERE
PRIVILEGED TO HAVE 94 EXPERT
SPEAKERS FROM LEADING
PHARMACEUTICAL AND ACADEMIC
RESEARCH LABS.”
www.worldadc-usa.com +1 415 735 3289
2
adc@hansonwade.com Antibody Drug Conjugates
POST EVENT REPORT
CONFERENCE DAY 1,
SEPTEMBER 21 2017
CHAIR’S OPENING REMARKS:
SCOTT DYLLA (SD)
SD from Stemcentrx provided opening remarks for 8th World ADC conference. According to him, there
are currently 32 companies working on ADCs with 105 clinical candidates in 2017. He predicts that the
4 out of 25 candidates (16% success rate) will be approved with overall possibility of 7+ ADCs getting
FDA approvals by 2020. This includes 3 new candidates namely sacituzumab (a-TROP-2-SN38 for
triple negative breast cancers), mirvetuximab (folate expressing), and rovalpituzumab (a-DLL3-PBD
conjugate against small cell lung carcinoma).
SD concluded his opening remarks by summarizing Abbvie-stemcentrx’s efforts of combining ADCs
with chemotherapeutic drugs (cisplatin, topotecan etc.) against solid tumors with special focus on
maximizing therapeutic index, minimizing off-target toxicities (with respect to PBD payload), and
overcoming drug resistance to current payloads.
“HE PREDICTS THAT THE 4 OUT OF 25
CANDIDATES (16% SUCCESS RATE) WILL BE
APPROVED WITH OVERALL POSSIBILITY OF
7+ ADCS GETTING FDA APPROVALS BY 2020.”
www.worldadc-usa.com +1 415 735 3289
3
adc@hansonwade.com Antibody Drug Conjugates
CONFERENCE DAY 1,
SEPTEMBER 21 2017
KEYNOTE SPEAKERS
SPEAKER 1: SPEAKER 2:
JOHN LAMBERT (JL) PUJA SAPRA (PS)
Antibody Drug Conjugates: Development of Several Classes of
Current Status and Future Directions DNA-Damaging ADCs
JL began his talk by focusing on historical (combination PS first talked about Pfizer’s efforts on targeted drug
therapy and mylotarg) and fundamental aspects of ADC delivery using nanoparticles and ADCs. She also gave
development. He gave some really interesting facts such as an outline describing site-specific vs. random methods
i) 1012 cancer cells were present in given mass of tumor, ii) of bio-conjugations. However, the main focus of her talk
≈0.01% of the ADC is internalized in the tumor as compared was mylotarg and besponza. Both FDA approved ADCs
to given dose. Therefore, in order to obtain complete containing calicheamicin as a warhead against hematological
remission in cancer patient one needs to kill ≈99% of the malignancies targeting AML and ALL. Previously Pfizer
cancer cells. According to JL, poor tumor penetration (due discontinued mylotarg from the market due to its undesirable
to slow internalization), compromised PK/PD properties, side effects. PS added that instead of giving high doses of
and non-specific distribution were major hurdles in ADC mylotarg fractionated dosing of this ADC has shown much-
development. Altering FcRn, masking binding to normal improved efficacy resulting in reintroduction of this ADC. PS
tissues, more stable linkers, small protein domain+drug gave analogy of radiation therapy that does the same thing
(bicycle therapeutics) will provide long-term solutions to i.e. DNA double strand break. So, it has been thought that
above broad questions in the field. fractionated radiation therapy showed less than 20% adverse
effects as compared to continuous radiation.
JL suggested incorporation of sulfates (charged species)
onto linkers, new linker design that take advantage of PS switched her talk then to the preclinical research done on
bystander killing, and imine modified PBDs-ADCs showing calicheamicin containing ADC where her group has looked
superior activity over traditional PBD warhead. JL concluded into cGA5/STING recognition pathway that stimulated
his lecture by summarizing clinical development of type-1 IFN production and activated anti-tumor immunity.
mirvetuximab against FR-a (50% minimum expression) PS ended her lecture by showing some interesting results on
positive platinum resistant ovarian cancers. utilization of CPI dimers that can circumvent P-glycoprotein
associated multidrug resistance (MDR).
SPEAKER 3:
SPEAKER: RAKESH DIXIT (RD)
Minimizing off-target toxicity and improve targeting to tumor associated antigens
RD from MedImmune gave very interesting lecture focusing on translational challenges to attaining desirable clinical
therapeutic index and significance of both on and off target toxicities. According to him the mechanism by which recycling
of ADC back to the surface in the normal cell were crucial to control the off target effects. Liver, skin, and bone marrow were
main target organs for off-target toxicities. He emphasized that antibodies cannot be that specific. According to his studies if
ADC is showing off-target effects in monkeys then it will most likely to show these effects in humans as well. These off-target
toxicities were due to metabolism in hepatic, extra-hepatic tissues, pinocytosis, and non-specific interaction with fcY receptor
leading to thrombocytopenia.
RD discussed an example of anti-EphA2 (target expressed on multiple solid tumors) ADCs containing DM1, PBD, and tubulysins
as a payload types. In these case studies toxicities such as hemorrhagic blisters, skin toxicities, keratinocyte damage, kidney
and liver toxicities, pinocytosis dominates off-target mechanism. Some recommendations by RD: i) longer half life-better the
safety profiles (2 weeks half-life being ideal), ii) reduce the toxicity of warhead, iii) use of non-cleavable linkers, and iv) lower
mannose receptor binding in liver, bone marrow, and skin.
www.worldadc-usa.com +1 415 735 3289
4
adc@hansonwade.com Antibody Drug Conjugates
CONFERENCE DAY 1,
SEPTEMBER 21 2017
DISCOVERY STREAM
SPEAKER 1: SPEAKER 2:
HANS-GEORG LERCHEN (HGL) CAMPBELL BUNCE (CB)
Antibody-Drug conjugates with pyrrole- ThioBridge as a tool for the design,
based KSP inhibitors as novel payload class optimization and manufacture of ADCs
The main focus of HGL’s talk was about BAY-333, an inhibitor CB continued this session and discussed ThioBridge
of kinesin spindle protein as an ADC payload. The pyrrole that targets natural disulfides with highly reproducible
based KSP inhibitor can cause mitotic arrest with an EC50 conjugation profiles from mg to gm scales. This technology
of 1 nM. The main focus of this work was to introduce can modify various therapeutic antibodies with a DAR
new modifications in the parent structure of KSP inhibitor ranging from 0-8. The principle design is based on bis-
and identify correct position in the parent molecule for sulfone reagent that is selective for the cysteine sulfur atom
incorporating cleavable/non-cleavable linker. from a native disulfide.
BAY 333 was modified with longer chain thiol-maleimide Above reagent can undergo bisalkylation to conjugate both
linker at the specific position. BAY333 modified ADC was the thiols derived from single disulfide pair. The resulting
tested against TWEAK receptor (highly expressed in many reaction leads to covalent rebridging of disulfide bonds via a
solid tumors) present in non-small cell lung carcinomas three-carbon bridge, leaving the protein structurally intact,
xenograft mice model. ADC with 2,4,5 mg/kg illustrated CB explained.
complete tumor remission in PDX mice model (Fig 1).
SPEAKER 3:
PHILIP HOWARD (PH)
PBD/ADC update
PH concluded the discovery stream lecture where he mainly emphasized on the PBD’s as an excellent payload class, clinical
progress, and new PBD derivatives for future applications. PH supports the observation made by RD that PBD is excellent
payload since it kills everything (≈99% cancer cell) that is extremely critical to obtain complete tumor remission in patients.
PBD also possess lack of cross-resistance with cisplatin. However, Seattle Genetics (SG) has discontinued one of the promising
CD33 targeting PBD ADC due to its undesired side effects and death of several patients due to its off-target effects (Fig 2).
However, another clinical candidate ADCT-402 (ADC therapeutics) targeting CD19 receptor that possess Tesirine-PEG8 linker
has shown promising results with bystander killing effect on antigen negative cells demonstrating its superiority over previous
SG construct. PH ended his talk by showing some new chemical handles that can be use to modify PBD’s either at C2-methyl
or C7 position or the modification can also be done at the middle portion of the PBD dimer through alkyne bridging (Fig 3).
Fig 1: BAY 333 scaffold Fig 2: Middle portion of PBD dimer modifcation Fig 3: C7 linker installment site
www.worldadc-usa.com +1 415 735 3289
5
adc@hansonwade.com Antibody Drug Conjugates
CONFERENCE DAY 1,
SEPTEMBER 21 2017
DISCOVERY STREAM
SPEAKER 4: SPEAKER 5:
RUSSELL DUSTIN (RD) BRUCE HAN (BH)
Enabling the next generation of Site-specific conjugation: Improving
calicheamicin-based antibody-drug homogeneity and other druggability
conjugates properties of antibody-drug conjugates
Rational design of aminohexose-linked calicheamicin BH from Newbio therapeutics conducted this session by
linker payload was the main focus of RD’s talk. RD and explaining the importance of site-specific conjugations.
his group found that the Bergmann cyclization reaction Newbio therapeutic has developed new tridentate linker
gave undesirable results when they were attempting to composed of 2 maleimide groups per tridentate linker which
create N-acetyl modification calicheamicin. This form of in turn can be reacted with reduced interchain disulfides. This
molecule is more potent but poorly tolerated. Introducing method doesn’t require any antibody engineering and allows
these modifications was possible by i) introducing EDCl as high purity products with DAR of 4.
a thiolate scavenger, ii) facile 2-pyridyl disulfide exchange
or iii) use of PFP carbonate that reacts readily with HOAt BH extended his talk by disclosing some of the new
at RT, iv) find a more co-operative aryl disulfide. The newly derivatives of dolastatin 10 with useful modifications that
designed derivative with above modifications has lead showed enhanced or superior biological activities against
to potent ADC showing superior in vivo properties against HER positive breast cancer. BH concluded his speech by
CD33 overexpressing xenograft models. Therefore, a critical showing the potential ADC clinical candidates in newbio
improvement in the chemistries of the linker attachment therapeutics pipeline.
and disulfide exchange has enabled safe and efficient
exploration of this new class of calicheamicin.
SPEAKER 6:
DAVID RABUKA (DR)
Latest advances developing antibody drug conjugates and other bioconjugates using SMARTag technology
DR from catalent biopharma concluded this afternoon discovery session. DR discussed site-specific conjugation strategy
based on incorporation of formylglycine amino acid modification in the structure of humanized antibody. The resulting
aldehyde can be readily reacted with aminoxy or hydrazine functionalized or hydrazine-iso-pictet spengler modified payload
of interest. The resulting ADC showed superior in vitro and in vivo targeting properties with DAR of 2, DR added. According to
him formylglycine containing humanized antibodies can be manufactured in mg to gm scale without any difficulties.
THEREFORE, A CRITICAL IMPROVEMENT IN THE
CHEMISTRIES OF THE LINKER ATTACHMENT AND
DISULFIDE EXCHANGE HAS ENABLED SAFE AND EFFICIENT
EXPLORATION OF THIS NEW CLASS OF CALICHEAMICIN.
www.worldadc-usa.com +1 415 735 3289
6
adc@hansonwade.com Antibody Drug Conjugates
CONFERENCE DAY 1,
SEPTEMBER 21 2017
5 MINUTE SHORT-FIRE
POSTER PRESENTATION TALKS
SPEAKER 1: SPEAKER 1:
CHRISTOFFER NIELSON (CN) ROGER SCHIBLI (RS)
ADCM: the next generation Active T Enzymatic site-specific conjugation of
argeting Technology engineered and native antibodies
CN demonstrated ADC mediated targeting of novel target, RS showed using microbial transglutaminase (MTG) that they
collagen receptor uPARAP. This target has been found to could engineer antibodies with various functional substrates
be unregulated in sarcomas, glioblastoma, and certain at glutamine residue Q295 and lysine residue K288/290 and
leukemia’s while showing limited expression in normal K340. This was achieved by combining immobilized MTG
tissues. mAb against uPARAP-vc-PAB containing MMAE with dual modifications on engineered antibody conjugation
showed robust responses in subcutaneous model of solid of fluorescent dye or radiolabelling agent or payload of
tumors. Targeting this antigen with PBD and duocarmycins is choice. RS claimed that this method enabled site-specific
currently undergoing in his laboratory. payload attachment to native antibodies, thus generating
well-defined ADCs that have native IgG structure.
“CHRISTOFFER NIELSON DEMONSTRATED ADC MEDIATED
TARGETING OF NOVEL TARGET, COLLAGEN RECEPTOR
UPARAP. THIS TARGET HAS BEEN FOUND TO BE UNREGULATED
IN SARCOMAS, GLIOBLASTOMA, AND CERTAIN LEUKEMIA’S
WHILE SHOWING LIMITED EXPRESSION IN NORMAL TISSUES.”
www.worldadc-usa.com +1 415 735 3289
7
adc@hansonwade.com Antibody Drug Conjugates
CONFERENCE DAY 1,
SEPTEMBER 21 2017
EVENING PLENARY SESSION
SPEAKER 1: SPEAKER 2:
CHARLIE JOHNSON (CJ) PETER DRAGOVICH (PD)
Lock-release: Delivering a solid phase Next Generation Antibody-Drug Conjugates
solution to conjugators
PD continued this session and showed some really interesting
Reaching an optimal DAR and limiting aggregation to data on CPI dimers as DNA crosslinking payload class. In
acceptable levels are closely linked, and CJ’s Lock-Release first part of his talk he focused on bizeclesin, CPI dimers,
technology has proven to be a key product enabler in and potential attachment sites for introducing linkers for
meeting this twin challenge. Lock Release facilitates ADC conjugation. ADCs prepared using CPI dimers were
maximum cell killing efficacy at higher DARs and at a tested against locus 6 complex (Ly6E) protein overexpressed
quality-minimal aggregate and unbound drug-suitable in triple negative breast and non-small cell lung cancers
for pivotal pre-clinical and clinical testing. CJ emphasized (NSCLC). Minimum efficacy dose (MED) of 1.5 and 0.5 mg/
that patented lock-release technology results in fast, simple kg in monkeys showed superior antitumor activity when CPI
and robust conjugation processes, with the potential to was used as payload over MMAE. Interestingly, linkerless
eliminate several process steps whilst enhancing product CPI-dimer showed potent activity in p-glycoprotein
quality. ‘Lock-Release’ aggregation control technology is a overexpressing tumor model. Dosing profile of 2 mg/kg was
key driver behind expansion into clinical & commercial drug well tolerated. ADC consisting of CPI-dimer showed kidney
manufacturing, CJ added. fibrosis at this single dose, PD added.
SPEAKER 3: SPEAKER 4:
ANDREAS PAHL (AP) DAVID TICE (DT)
Antibody Targeted Amanitin Conjugates The resistible ADC-Let us count the ways
(ATAC): Expanding the ADC landscape with a
new payload targeting RNA polymerase II DT gave some thought provoking ways by which resistance
against ADCs can occur. According to him resistance by
AP continued to show interesting data on ATAC in this year’s resilient cancer cells has been now evidenced in many cases.
conference as well. Amanitin has many plus points such as Innate/acquired resistance to EGFR inhibitors, resistance
it can kill quiescent (slowly dividing) tumor/stem cells. Anti- against immunotherapies and trastuzumab can occur via
EpCAM ADC showed EC50 of 0.26 nM against cancer stem many mechanisms. Preclinical, omics, and bioinformatics
cells. ATAC’s are effective on low expressed targets and p53 data showed significant down regulation of antigens
gene deletion showed 10-fold enhancement to EpCAM- targeted by ADCs particularly PBD associated resistance he
amanitin-ADCs, AP added. Proprietary ATAC technology pointed out. He pointed out many mechanisms by which
has been tested against BCMA and HDP-101 overexpressing resistance to ADC can occur. Hep42 and Hep3B target
antigen making it a strong case against multiple myeloma lost on the cell surface, protein processing altered, up
were cancer cells were slowly proliferating. AP and his team regulation of drug efflux pumps making T-DM1 treatment
tested these conjugates in many xenograft models and unresponsive, increase in drug metabolizing enzymes
monkey’s showing superior efficacies with no liver toxicities. AP such as up regulation of cytochrome P450 and a-keto-
ended his talk by showing an interest to apply ATAC against reductase. After the treatment with PBD and tubulysins
CD138 positive cancers and begin preclinical trials in 2018. (DNA cross-linking agents), mutation in DNA repair pathway
has altered apoptosis and survival signaling pathways. In
another case study where DT and his team were assessing
PBD ADCs against BCMA overexpressing tumors at 0.1 mg/
kg dose showed innate resistance to this ADC with non-
permeable payload (PBD in this case). This resistance is not
due to defective ADC trafficking or lack of expression of the
lysosomal transporter protein. This transport is highly payload
specific. Acquired resistance to T-DM1 was also observed with
SLC46A3 loss in another case study.
www.worldadc-usa.com +1 415 735 3289
8
adc@hansonwade.com Antibody Drug ConjugatesPOST EVENT REPORT
CONFERENCE DAY 2,
SEPTEMBER 22 2017
CHAIR’S OPENING REMARKS:
SCOTT DYLLA (SD)
SD has been fabulous in providing meaningful opening remarks for the second day. He started this by
asking hard questions such as why have previous ADC clinical candidates have failed. To summarize
following were some of the factors: lack of therapeutic window, unsafe at the doses lower than
expected, insufficient efficacy at the maximum tolerated dose (MTD), suboptimal trial design (all
common vs. targeted trials), inability to identify/enrich responders vs. non-responders, efficacious
exposure of ADCs at maximum therapeutic index, relevant species cross-reactivity-affinity for given
target, internalization and expression pattern of a given biological target.
“SCOTT DYLLA HAS BEEN FABULOUS IN PROVIDING
MEANINGFUL OPENING REMARKS FOR THE
SECOND DAY. HE STARTED THIS BY ASKING HARD
QUESTIONS SUCH AS WHY HAVE PREVIOUS ADC
CLINICAL CANDIDATES HAVE FAILED.”
www.worldadc-usa.com +1 415 735 3289
9
adc@hansonwade.com Antibody Drug ConjugatesCONFERENCE DAY 2,
SEPTEMBER 22 2017
KEYNOTE SPEAKERS
SPEAKER 1: SPEAKER 2:
ROBERT LYON (RL) DAVID THURSTON (DT)
Design principles for maximizing the Drug Pyridinobenzodiazepine (PDD):
Delivery Efficiency and therapeutic A novel class of ADC payloads
index of ADCs
In this lecture, DT disclosed Femtogenix’s new generation of
RL began this interesting talk by giving an example of PBD’s called PDD. PDD possess DNA non-covalent sequence
Adcetris (average DAR of 4 drugs/antibody). High drug recognition component tether to PBD cross-linking site. DT
loading through random conjugation chemistries often studied Femtogenix’s clinical candidate FGX-2-62 for its
leads to faster clearance of antibody-drug conjugate. monoalkylation vs. cross-linking properties by comparing it
Accelerated clearance of ADC often results in greater non- with PBD’s using DNA finger printing and FRET experiments.
specific uptake (macrophage, hepatic endothelial cells). According to these experiments, PDD has an additional DNA
Hydrophobicity co-relates very well with the faster plasma binding site plus the common site (both common for PBD
clearance of ADCs, RL added. Can we mask the hydrophobic and PDD). Moreover, nuclear penetration and extent of DNA
drug-linker component of ADCs? This can be done either by damage of FGX-2-62 has found to be similar as compared to
removing hydrophobic region of molecule or by studying the PBD conjugated ADCs.
effect of linear or branch poly(ethylene glycol) on the ADC
pharmacokinetics. RL and co-workers have demonstrated DT and co-workers plan to use PDD conjugated ADCs against
that the PEG8, and PEG12 is the ideal PEG length to be TRA (carbohydrate based antigen) overexpressing embryonic
incorporated in these constructs. In addition to PEG they cancer stem cells and metastatic tumors with initial in vitro
have introduced glucuronide- release trigger. The clearance EC50 of 0.47-0.67 nM.
properties of these ADCs co-relate very well however, ADCs
that have faster clearance showed more toxic side effects.
ADCs that lack PEG showed bone-marrow depletion. ADCs
possessing PEGylated glucuronide linker showed greater
plasma exposure and drives sustained tumor uptake. RL
concluded that the hydrophobicity is mainly responsible for
off-target effects and fast clearance.
SPEAKER 3: SPEAKER 4:
SHARON MCGONIGLE (SM) HUI LI (HL)
Chlorotoxin in peptide drug conjugates: Preclinical Development of Superior ADCs
Improved understanding of tumor targeting Incorporating Novel Linker and Warhead Designs
Chlorotoxin is well known tumor-targeting peptide isolated HL concluded this morning session by giving brief information
from scorpion venom. It has been proved to be efficacious about the robust platform for screening antibodies to ADC
for tumor specific uptake in glioma patients. It can also block leads in 2 months, from target IND within 2 years of research.
chloride ion channel that is non-toxic to humans. Chlorotoxin HL showed promising data on several ADC candidates
has also been used for surgical removal of glioma tumors in showing superior PK/PD and antitumor properties. HL ended
children by conjugating it to near infrared dye SM added. In his talk by discussing multifunctional ADCs.
order to enhance the therapeutic potential of chlorotoxin, the
peptide has been conjugate to cryptophycin as a payload
class through dimethyl disulfide linker. Chlorotoxin conjugated
cryptophycin mediates binding of chlorotoxin to neuropilin 1.
This binding event occurs through c-terminal arginine residue
that in turn mediates its uptake in cancer cells. However, mode
of action by which it crosses blood brain barrier is still unknown,
SM concluded.
www.worldadc-usa.com +1 415 735 3289
10
adc@hansonwade.com Antibody Drug ConjugatesCONFERENCE DAY 2,
SEPTEMBER 22 2017
DISCOVERY STREAM
SPEAKER 1: SPEAKER 2:
MARIA JARAMILLO (MJ) JACK SADOWSKY (JS)
Explore a novel-screening platform for Conjugation Development and Mechanistic
development of antibody-drug conjugates Analysis of Disulfide-Linked THIOMABTM
against novel targets Antibody-Drug Conjugates
MJ started her interesting talk by enlisting some of the JS from Genentech gave a lecture on mechanistic insights on
key aspects for screening of realistic targets for ADC THIOMAB linked ADCs. JS categorized linkers into 4 main types:
development. The approach for novel target selection i) peptide-val-cit, ii) indirect-amide-disulfide, iii) non-cleavable-
by MJ relies upon mRNA expression, microarray data, SMCC and iv) direct-disulfide. JS and co-worker previously
RNA sequencing, comparison of cell surface protein showed that (Pillow et al. 2017) direct disulfide conjugates are
vs. secreted mRNA (proteomics), and glycoproteomics more efficacious than indirect disulfides however, non-cleavable
(biological nature of target, functional relevance, network linker is stable for 7 days while the indirect one is not stable.
of genes). Humanized mAb were created against specific Nitro-substituted pyridyl group introduction adjacent to disulfide
target robustly using phage display technology. Antibody gave improved stability but it is highly dependent upon site of
selection largely depends upon tumor selection, affinity/ disulfide attachment. General approach to address this issue
avidity, internalization, epitope characterization-ligand was to create more hindered dimethyl substituted disulfides.
binding, and species cross-reactivity. MJ elaborated This enabled highly stable and efficacious ADC conjugate. JS
her talk by giving a case study of Axl targeted ADCs. Axl presented very interesting hypothesis that ADC were internalized
is overexpressed in many cancers. It is a tyrosine kinase in lysosomal or endosomal compartment that is mostly
receptor found also in cancer stem cell phenotype. oxidative so how were disulfide linked ADCs activated in these
Humanized chimeric version of anti-Axl was generated. compartments? To test this hypothesis FRET probe composed
Axl-SMCC-DM1 showed promising biological activities of TAMRA and BODIPY was developed. Upon internalization
in xenograft tumor model. MJ ended her talk by giving increase fluorescence from the TAMRA were observed illustrating
another example of Axl-biparatopic ADC showing 10-100x efficient cleavage of disulfide inside lysosomal compartments.
times improved activity over monospecific IgG. Disulfide cleavage was attributed to the activity of proteases
such as cathepsins, JS concluded.
SPEAKER 3: SPEAKER 4:
JIMMY BAO (JB) JUTTA WANNER (JW)
Cancer Target Atlas for Tunable Drug Conjugates (TDCs):
Antibody-drug Conjugates Holistically Redesigning Drug Conjugates
JB represented Abmart. His company has developed a JW concluded this interesting session by describing their
massively parallel mAb array (Human Membrane Proteome proprietary linker technology. Linker composed of silylether
MabArray) for measuring thousands of cancer and immune (silicon) can undergo pH specific cleavage in sequential
cell surface proteins. His approach makes use of hybridoma manner inside cancer cells and holds high stability in
mab array that has identified close to 3,000 mAb’s for each circulation. JW’s team have devised fab/small molecule
cancer type. His company also provides support for studying targeting ligands that possess better tumor penetration over
internalization of antibodies using FACS, immunoprecipitation/ antibody therapeutics. Her team developed a small toolbox
mass spec based identification, and in vitro/in vivo assessment of payloads that were attached via “ligand-spacer-adapter-
of ADCs. Using this approach JB and his company has Si-linker-payload” format. Multiple silicon linkers with varied
identified 8 novel targets associated with cancer stem cell hydrolysis profiles were developed. Pyrimidine-Si-linker-folate
marker, lung (mab 116), esophageal (mab 104 and 253), and demonstrated rapid payload release profiles. JW and her
liver cancers (mabB85 and mab 222). JB’s company has team are currently developing Folate-a-TDCs against ovarian
experience working on multiple pre-clinical ADC molecules cancers using vinblastine-silynol-folate constructs.
currently being under development.
www.worldadc-usa.com +1 415 735 3289
11
adc@hansonwade.com Antibody Drug ConjugatesCONFERENCE DAY 2,
SEPTEMBER 22 2017
DISCOVERY STREAM (SUB SESSIONS)
SPEAKER 1: SPEAKER 2:
JON WEIDANZ (JW) JIM CHRISTIE (JC)
TCR-like Antibody-Drug Conjugates Non-natural amino acids for simple and
Mediated Killing of Tumor Cells with Low efficient production of ADCs
peptide/HLA targets
JC started this lecture with the thought of discovering
JW began afternoon session with a very interesting target novel non-natural amino acid (NNAA) bearing functional
such as tumor specific HLA-peptide target. Initially in this field, group that can provide favorable PK/PD, stability, limited
peptide based vaccine was designed that can recognize HLA hydrophobicity, and faster conjugation of payloads. In this
peptide and generate T-cell receptor (TCR) like antibodies. TCR work he reports on utilizing pyrrolysyl-tRNA-synthetase
like antibodies that can undergo ADCC mediated cell death. systems to incorporate NNAA’s bearing cyclic dienes group
However, the response against HLA peptide target was not that could allow efficient bio-conjugation.
robust due to low copy no of this target (such as 2,000/cell).
Therefore, developing TCR-like ADC could be very attractive, His group at MedImmune found that the incorporation
JW said. These observations lead to the development of of CP2 like dienes is highly specific for reactions with thiols
duocarmycin conjugated TCR-ADC that targeted low copy giving stable product without the loss of payload for 7 days.
number (1,000/cell) HLA peptide target. Due to low copy According to him, cyclic dienes were overlooked since they
number and target docking orientation hypothesis the above are not bio-orthogonal however; they react faster in aqueous
ADC showed compromised activity. Finally, sortase enzyme conditions with thiols with very high specificity. CP2 like cyclic
mediated site-specific conjugation of anthracyclins showed dienes incorporated ADCs were found to be extremely potent
EC50 of 195 pM in 4T1 tumor model while 900 pM EC50 was in vitro and in vivo when compared against thiol-maleimide
obtained in low copy number (500/cell) tumor cells. or using other non-selective chemistries, JC ended (Fig 1).
SPEAKER 3:
TRAVIS YOUNG (TY)
Repurposing an imaging agent to target a bispecific antibody to prostate cancer
TY concluded this interesting session on high note. His team has developed immunotherapy-based approach against PSMA
overexpressing prostate cancers. Construct is composed of “Bispecific antibody-stable/non-cleavable linker-DUPA-ligand”. Monovalent
CD33 binding to bispecific antibody can be optimized through NNAA incorporation - this binding recruits immune cells (ADCC). At the
same time DUPA (high affinity PSMA binding ligand) binds with high specificity to PSMA on the prostate cancer cell and then immune
recruitment leads to selective lysis of tumor cells. This construct has very high stability and showed excellent anti-tumor activity both in
vitro and in vivo xenograft model. This construct shows potent activity against many MDR positive cancers, TY added (Fig 2).
Fig 1: CP2 non-natural amino acid Fig 2: DUPA
www.worldadc-usa.com +1 415 735 3289
12
adc@hansonwade.com Antibody Drug ConjugatesCONFERENCE DAY 2,
SEPTEMBER 22 2017
PART OF SCIENTIFIC PROGRAM
SPEAKER 1: SPEAKER 1:
DANIELA TOMAZELA (DT) BEN-QUAN SHEN (BS)
Developing the magic bullet outside Preclinical ADME Characterization of
oncology: An analytical perspective THIOMABTM-Antibiotic conjugates (TAC)
to support clinical development of TAC for
DT focuses her talk mainly on the delivery of glucocorticoids treating StaphA infectious disease
using ADCs. DT and her colleagues used Ambrx unnatural
amino acid incorporation platform composed of aryl- BS gave a last lecture of the 8th World ADC conference.
azide to tag antibody of interest that in turn reacted with He showed very unique application of ADCs for delivering
suitable alkyne functionalized with various glucocorticoids antibiotic selectively to the StaphA infected cells using
(Dexamethasone, Budesonide and Fluticasone) through THIOMABTM-Antibiotic conjugates (TAC). 70% of the
phosphate linker system that was found to be stable for 21 StaphA population is sensitive to methicillin treatment and
days at 37oC. However, in vivo screening showed dramatic 30% is resistant to this antibiotic. Many antibiotics possess
release of payload in plasma showing unstable cathepsin very high MIC in the range of 100-400 MIC. To overcome
cleavable ADC. The peptide mapping analysis showed this problem TAC was prepared using many known
clipping at amino acid site. DT showed these results with antibiotics such as rifamycin, daptomycin, and vancomycin
respect to anti-CD74-phosphate linker-Budesonide construct. and targeted against highly conserved antigen found in
In addition, above construct showed several off-target many StaphA strains using THIOMAB. TAC prepared using
ADC associated proteins due to instability of the antibody. many antibiotics showed linear PK without the presence of
Monoclonal anti-CD74 antibody showed non-linear PK target while non-linear PK was observed where bacterial
profiles, tissue disposition was 34% in spleen and liver target antigen was present. Overall TAC showed promising
showing off-target accumulation, and payload was found in preclinical in vitro and in vivo data against many resistant
supernatant and in cell pellet. Overall, DT showed unstable bacterial strains demonstrating superiority of this approach
ADC with proteolysis of antibody. to treat bacterial infections.
THANKS TO ALL SPEAKERS AT
WORLD ADC SAN DIEGO
WORLD ADC BERLIN WORLD ADC SAN DIEGO
26-28 FEBRUARY, BERLIN 12-14 NOVEMBER, SAN DIEGO
WWW.WORLDADC-EUROPE.COM WWW.WORLDADC-USA.COM
www.worldadc-usa.com +1 415 735 3289
13
adc@hansonwade.com Antibody Drug ConjugatesYou can also read
