Design Principles for Maximizing the Drug Delivery Efficiency and Therapeutic Index of ADCs

Transcription

1 Design Principles for Maximizing the Drug Delivery Efficiency and Therapeutic Index of ADCs World ADC 217 San Diego Robert Lyon Sr. Director, Chemistry

2 Themes of the presentation This represents the desired fate of an ADC: What else can happen to ADC in plasma (step 1) that may prevent it from reaching step 2? How does that affect the therapeutic index? How can ADCs be designed to maximize the fraction that follows the desired path? 2 Confidential

3 Cysteine-based conjugation for Adcetris produces an average of 4 drugs / antibody 8 thiols per antibody Full reduction (excess TCEP) IgG1 Partial reduction (limiting TCEP) Conjugation with maleimido-drug linker thiols per antibody 8 drugs per antibody drugs per antibody (8) Why not use uniform ADCs with 8 drugs? Hydrophobic Interaction Chromatography () (2) (4) (6) (8) min time (min) W2996 Extraction at 28 nm min time (min) W2996 Extraction at 28 nm 3 Confidential

4 c on centration ( mg/ ml) High drug loading can result in faster clearance Conjugation with mc-vc-mmae: Antibody / ADC Pharmacokinetics 1 mc-vc-mmae loading reduced disulfide time (days) 8 4 reduced disulfides 4 Confidential Hamblett,K et al., Clinical Cancer Res. 24, 1,

5 [A b ] (m g /m l) Accelerated clearance of an ADC may be due to greater non-specific uptake Detection of hepatic uptake by IHC: 1 antibody 1 1 hepatic endothelium macrophages a n tib o d y A D C tim e (d a y s ) ADC 5 Confidential

6 [A b ] (m g /m l) Plasma clearance correlates with the apparent hydrophobicity of the ADC Auristatin ADCs with 8 drugs per antibody evaluated for apparent hydrophobicity and pharmacokinetics Hydrophobicity Mouse Pharmacokinetics (antibody concentration in plasma) 1 ADC: 28 nm HIC ADC 1 native h1f6 Auristatin T 1 mcmmaf mc-vc-mmaf min retention time (minutes) W2996 Extraction at 28 nm h1f6; ; 3/13/212 7:13:4 PM PDT W2996 Extraction at 28 nm h1f6-1251; ; 3/13/212 7:52:57 PM PDT W2996 Extraction at 28 nm h1f6-488; ; 3/13/212 8:12:54 PM PDT W2996 Extraction at 28 nm h1f6-1269; ; 3/13/212 8:32:51 PM PDT tim e (d a y s ) Hydrophobic Interaction Chromatography retention time predicts pharmacokinetics reasonably well 6 Confidential Lyon, R. P. et al. Nature Biotechnology 33, (215).

7 Can we mask the hydrophobic drug-linker component of an ADC? Hydrophobic patch introduced by drug conjugation in the IgG hinge Hydrophobicity masked by PEG PEG PEG is a hydrophilic polymer Low toxicity We can vary the length of the chain to tune the effect 7 Confidential

8 T o ta l A n tib o d y (m g /m l) Effect of PEG on ADC pharmacokinetics Glucuronide-MMAE drug-linker chosen for proof-of-concept 1 Glucuronide release trigger MMAE tim e (d a y s ) u n c o n ju g a te d DPR maleimide (imparts stability) A D C w ith o u t P E G 8 Confidential

9 T o ta l A n tib o d y (m g /m l) Effect of PEG on ADC pharmacokinetics Introduction of PEG 24 restores pharmacokinetics of parental antibody 1 Glucuronide release trigger MMAE tim e (d a y s ) u n c o n ju g a te d A D C w ith o u t P E G A D C w ith 2 4 P E G u n its DPR maleimide (imparts stability) PEG 24 9 Confidential

10 T o ta l A n tib o d y (m g /m l) Effect of PEG on ADC pharmacokinetics Introduction of PEG 24 restores pharmacokinetics of parental antibody Detection of hepatic uptake by IHC: tim e (d a y s ) u n c o n ju g a te d A D C w ith o u t P E G A D C w ith 2 4 P E G u n its 1 Confidential

11 T o ta l A n tib o d y (m g /m l) Effect of PEG on ADC pharmacokinetics Continuum of PEG length produces continuum of ADC clearance rates tim e (d a y s ) continuum of PEG lengths produces continuum of ADC clearance rates u n c o n ju g a te d P E G y la te d A D C s A D C w ith o u t P E G 2 # 4 o f 8 P E G 1 2 u n its Confidential

12 T o ta l A n tib o d y (m g /m l) C le a ra n c e (m L k g - 1 d ay - 1 ) Effect of PEG on ADC pharmacokinetics A D C c le a r a n c e a s a fu n c tio n o f P E G s iz e tim e (d a y s ) P E G y la te d A D C s P E G le n g th A D C w ith o u t P E G # o f P E G u n its These ADCs provide a set of tools to study the role of clearance rate on ADC pharmacology / toxicology 12 Confidential

13 T o ta l A n tib o d y (m g /m l) P e rc e n t S u rv iv a l* Clearance correlates with acute toxicity Faster clearance leads to greater toxicity Survival following 2 mg/kg dose tim e (d a y s ) P E G y la te d A D C s A D C w ith o u t P E G # 4 o f 8 P E G 1 2 u n its D a y s * e x c lu d in g p la n n e d s a c r ific e s a t S D 8 a n d S D 2 9 (All ADCs tolerated at 1 mg/kg dose) 13 Confidential

14 n g M M A E /g tis s u e Why are faster clearing ADCs more toxic? MMAE concentrations following 3 mg/kg dose of ADC L iv e r 3 S p le e n d a y s ADC catabolism Fast ADC catabolism d a y s Fast conversion of conjugated drug to free drug 14 Confidential

15 n g M M A E /g tis s u e n g M M A E /m L o f p la s m a Why are faster clearing ADCs more toxic? MMAE concentrations following 3 mg/kg dose of ADC 1 5 B o n e M a r r o w.3 P la s m a d a y s ADC catabolism Fast ADC catabolism d a y s Fast conversion of conjugated drug to free drug 15 Confidential

16 Histopathology reveals continuum of bone marrow depletion Rat bone marrow (sternum) 1 week post-dose 2 mg/kg untreated (4 days post-dose) 16 Confidential

17 P la te le t C o u n t (1 3 /m L ) N e u tro p h il C o u n t (p e r m L ) A b s R e tic u lo c y te (1 3 /m L ) A b s. E o s in p h il (p e r m L ) Hematology reflects bone marrow effects 6 R e tic u lo c y te s 1 mg/kg E o s in o p h ils S tu d y D a y 1 P la te le ts untreated S tu d y D a y N e u tr o p h ils mg/kg S tu d y D a y S tu d y D a y 17 Confidential

18 A L P (U /L ) A S T (U /L ) A L T (U /L ) Serum chemistry toxicity markers also follow the clearance continuum Mild elevations 1 week after a 1 mg/kg dose 4 A lk a lin e P h o s p h a ta s e 3 A s p a rta te A m in o tra n s fe ra s e 1 A la n in e A m in o tra n s fe ra s e Confidential

19 C o n c e n tr a tio n (n g /m L ) C o n c e n tr a tio n (n g /m L ) In murine xenograft models, greater plasma exposure drives sustained tumor uptake Radiolabeled anti-cd3 ADCs dosed at 1 mg/kg in L54cy model of Hodgkin lymphoma 1 Plasma pharmacokinetics 1 Tumor uptake T im e (d a y s ) T im e (d a y s ) Magnitude of pharmacokinetic differences are smaller in mice than in rats 19 Confidential

20 m e a n tu m o r v o lu m e (m m 3 ) re m a in in g m ic e Clearance correlates well with activity Slower clearance leads to greater antitumor activity Anti-CD19 ADCs dosed at 3 mg/kg in RL model of DLBCL d a y s p o s t im p la n t untreated d a y s p o s t tu m o r im p la n t 4 mice sacrificed when tumors reach 1 mm 3 2 Confidential

21 % d r u g r e m a in in g Understanding the relative impact of stability and clearance Four ADCs to interrogate plasma stability and non-specific uptake ADC incubation in plasma d a y s p o s t d o s e mc-val-cit- MMAE mdpr-val-cit- MMAE mc-(peg)- glucuronide- MMAE mdpr-(peg)- glucuronide- MMAE 21 Confidential

22 ] n M [M M A E ] n M [M M A E ] n M [M M A E ] n M [M M A E ] n M Free MMAE tissue profiles from DAR 8 ADCs MMAE C max in tissues dominated by fast ADC clearance, not drug-linker stability mc linkers (prone to maleimide loss) Δc max <2 fold mdpr linkers (completely stable) Val-Cit linkers b o n e m a rr o w 5 liv e r s p le e n 5 ly m p h n o d e (ADCs clear quickly) liv e r s p le e n s p le e n ly m p h 1 5n o d e ly 2 m4p h 6n o d8 e Δc max 2 8 fold ly m p h n o d e 1 1 PEGylated Glucuronide linkers (ADCs clear slowly) 5 22 Confidential T im e (d a y s ) T im e (d a y s )

23 Percent CD48+ Plasma Cells New MMAE drug-linker applied to a new antigen: SGN-CD48A Anticipated IND in Q4 of 217 CD48: A validated multiple myeloma antigen 9% of MM patients 26% of examined MM patients were previously treated or relapsed MM Patient Number 23 Confidential

24 S u rv iv in g M ic e (% ) S u rv iv in g M ic e (% ) S u rv iv in g M ic e (% ) S u rv iv in g M ic e (% ) Preclinical activity models of SGN-CD48A E J M - 7 S tu d y (D a y -1 3 ) E J M - 7 S tu d y (D a y -1 3 ) 8 6 U n tre a te d D a y s P o s t T u m o r Im p la n t N C IH s tu d y (D a y -1 2 F IN A L ) D a y s P o s t T u m o r Im p la n t 8 U n tre a te d 6 h ( 8 ) [M D P R - P E G g lu c -M M A E ] 1 m g /k g UUntreated n a te d Non-binding ADC 1. mg/kg h (8 ) [M D P R -P E G 1 2 -g lu c -M M A E ] 1 m g /k g 4 h M E M (8 ) m g /k g h M E M (8 ) 1 m g /k g E J M - 7 S tu d y (D a y -1 3 ) Curative activity at 1 mg/kg in multiple disseminated models of MM EJM h M E M ( 8 ) [M D P R -P E G g lu c -M M A E ] m g /k g SGN-CD48A SGN-CD48A.33 mg/kg 1. mg/kg h (8 ) [M D P R -P E G 1 2 -g lu c -M M Ah E M] E1 Mm -1g /k 2g (8 ) 1 m g /k g h M E M (8 ) m g /k g 2 h M E M (8 ) 1 m g /k g D a y s P o s t T u m o r Im p la n t U n tre a te d h (8 ) [M D P R -P E G 1 2 -g lu c -M M A E ] 1 h M E M (8 ) m g /k g 4 h M E M (8 ) [M D P R -P E G g lu c -M M A E ] 1 m g /k g 2 NCI-H D a y s P o s t T u m o r Im p la n t MM.1R-luciferase 24 Confidential

25 Lessons from this work Higher released drug C max in tissues Increased toxicity Excessive ADC hydrophobicity Non-specific ADC interactions Faster ADC clearance in tissues Lower tumor exposure to ADC Decreased activity 25 Confidential

26 Lessons from this work Hydrophilic Excessive linkers ADC and hydrophobicity PEG masking Non-specific Highly ADC specific ADCs interactions Slow nonantigen Faster ADC clearance mediated in tissues clearance Higher Minimize released drug drug C C max in max in tissues tissues Maximize Lower tumor tumor exposure to exposure to ADC ADC Decreased Increased toxicity Decreased Increased activity 26 Confidential

27 Acknowledgments Scott Jeffrey Svetlana Doronina Tim Bovee Patrick Burke Translational Research Jessica Simmons, Haley Neff-LaFord, Cisco Zapata, Paul Pittman, Marti Anderson, Mechthild Jonas, Nagendra Chemuturi, Tim Lewis, Devra Olson Chemistry Joe Hamilton, Josh Hunter, Julia Cochran 27 Confidential Process Chemistry Minh Nguyen, Yunyu Mao, Malcolm Reider, Victoria Singletary, Wendel Doubleday Jonathan Drachman, Peter Senter, Dennis Benjamin

28 28 Partner with the Leader in ADCs Seattle Genetics is the global leader in ADC technology from bench to market o o o One of only 4 companies with a globally approved and marketed ADC: ADCETRIS (brentuximab vedotin) ~4% of current clinical stage ADCs utilize our technology ADC expertise remains central to our current and future business strategy Continually investing in broadening our extensive ADC platform o Antibodies, Payloads, Conjugation technologies Business development focused in 3 key areas: o Target-exclusive licensing of our diverse ADC platform for some level of strategic rights o In-licensing technologies that build on our ADC platform o In-licensing diverse research, pre-clinical & early clinical oncology programs (ADC / non-adc) Please contact our team via Roland Gendron o rgendron@seagen.com 28 Confidential