ADC payloads Educational session

40IN - A novel drug conjugate platform: Redefining the therapeutic window for ADCs

Presentation Number
40IN
Lecture Time
16:10 - 16:30
Speakers
  • John Babcook (Vancouver, CA)
Session Name
ADC payloads
Location
Room Scene AB, Paris Marriott Rive Gauche, Paris, France
Date
07.03.2018
Time
15:10 - 16:40
Authors
  • John Babcook (Vancouver, CA)
  • Rupert Davies (Seattle, US)
  • Stuart Barnscher (Vancouver, CA)
  • Jamie Rich (Vancouver, CA)
  • Kevin Yin (Vancouver, CA)
  • Vincent Fung (Vancouver, CA)
  • Geoff Winters (Vancouver, CA)
  • Graham Garnett (Vancouver, CA)
  • Patrick Kaminker (Seattle, US)
  • Kevin Hamblett (Seattle, US)

Abstract

Background

Antibody drug conjugates (ADCs) can offer significant benefit to patients suffering from a variety of solid and liquid tumors by combining the specificity of monoclonal antibodies and the cellular cytotoxicity of antineoplastic small molecules. While ADCs have tremendous potential, dose-limiting toxicity remains the largest barrier to robust patient responses. Through the utilization of proprietary protease cleavable N-acyl sulfonamide (NAcS) linked hemiasterlin and auristatin payloads, we have generated highly efficacious ADCs with improved therapeutic indices. Antibody drug conjugates (ADCs) can offer significant benefit to patients suffering from a variety of solid and liquid tumors by combining the specificity of monoclonal antibodies and the cellular cytotoxicity of antineoplastic small molecules. While ADCs have tremendous potential, dose-limiting toxicity remains the largest barrier to robust patient responses. Through the utilization of proprietary protease cleavable N-acyl sulfonamide (NAcS) linked hemiasterlin and auristatin payloads, we have generated highly efficacious ADCs with improved therapeutic indices.

Methods

Antibodies against HER2 and three additional known clinical targets were conjugated with our N-acyl sulfonamide auristatin (NAcS-ADCs) or with MMAE or DM4 controls (control ADCs) via cleavable linkers and used to assess in vitro binding and cytotoxicity. The therapeutic window of NAcS-ADCs and control ADCs was compared by assessing efficacy in mouse xenograft models and tolerability/pharmacokinetics in non-human primates (NHPs).

Results

NAcS-ADCs demonstrated similar in vitro binding and cytotoxicity compared to control ADCs. This activity was recapitulated in vivo with similar tumor growth inhibition in mouse xenograft models. In an NHP tolerability/pharmacokinetic study, the trastuzumab NAcS-ADC was well tolerated with a highest non-severely toxic dose (HNSTD) of 18 mg/kg, as compared to an HNSTD of 3 mg/kg for the trastuzumab MMAE control ADC. NAcS-ADCs for all three additional targets were well tolerated at doses of 18 mg/kg (single dose IV infusion) compared to their corresponding control ADCs that showed severe to life-threatening neutropenia at markedly lower doses.

Conclusions

The increase in tolerability and comparable efficacy of the NAcS-ADCs vs. the control ADCs against HER2 as well as three additional known clinical targets highlight the broad applicability of our novel NAcS-linked auristatin payload and its ability to expand the therapeutic window of ADC therapy.

Legal entity responsible for the study

Zymeworks Inc.

Disclosure

J. Babcook, R. Davies, S. Barnscher, J. Rich, K. Yin, V. Fung, G. Winters, G. Garnett, P. Kaminker, K. Hamblett: Employee of Zymeworks Inc. and have a financial interest in the company in the form of stock or stock-options.

Funding

Zymeworks Inc.

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