Engineering Antibody-Drug Conjugates

 

By combining the selectivity of targeted treatment with the cytotoxic potency of chemotherapy drugs, ADCs hold the promise to revolutionize disease treatment, especially for cancer. However, the path toward ADC success is not without challenges. Using lessons learned from the past decade of ADC development, scientists are developing strategies for the third-generation antibody-drug conjugates by selecting the right target antigens, designing new payloads, optimizing linkers and engineering conjugation chemistries.

In this first installment of our 2-part ADC program, PEGS Boston’s 9th Annual Engineering Antibody-Drug Conjugates invites scientists to present their design strategies in increasing therapeutic index through novel payloads, alternative platforms and new linker conjugation technologies. 

Final Agenda

WEDNESDAY, APRIL 10

7:15 am Registration and Morning Coffee

7:25 - 8:25 PANEL DISCUSSION: Women in Science – Inspired Professional and Personal Stories (Continental breakfast provided)

Moderator:

Jennifer-ChadwickJennifer S. Chadwick, PhD, Director of Biologic Development, BioAnalytix, Inc.; Co-chair, Mentors Advisors and Peers Program, Women In Bio, Boston Chapter


Panelists:

Joanna BrewerJoanna Brewer, PhD, VP, Platform Technologies, AdaptImmune


Charlotte A. RussellCharlotte A. Russell, MD, DMSc, Chief Medical Officer, Alligator Bioscience


Susan RichardsSusan Richards, PhD, Presidential Scientific Fellow, Translational Medicine Early Development, Sanofi R&D


Kristi SarnoKristi Sarno, Senior Director Business Development, Pfenex


NOVEL PAYLOADS AND NEW PLATFORMS

8:30 Chairperson’s Opening Remarks

Anton Neschadim, PhD, MBA, CEO, ImmunoBiochem Corporation

8:40 Enabling Silvestrol as a Novel Payload for Antibody-Drug Conjugates

Pillow_TomThomas Pillow, PhD, Senior Scientist, Discovery Chemistry, Genentech

This talk will focus on the discovery and optimization of silvestrol analogs as a novel class of antibody-drug conjugate payloads. The key learnings around drug metabolism will be discussed and how this can be avoided through engineering of the antibody or small molecule. Finally, several stable conjugates were advanced into in vivo studies and efficacy and safety data will be presented.

9:10 ADCs with Novel Kinesin Spindle Protein Inhibitor Payloads and a Tailor-Made Linker Chemistry

Lerchen_Hans-GeorgHans-Georg Lerchen, PhD, Chief Scientist, R&D Pharmaceuticals, Bayer AG

Inhibitors of kinesin spindle protein (KSPi) have been developed as a novel payload class in antibody-drug conjugates. To increase tumor selectivity of ADC metabolism, a tumor associated protease with a unique cleavage sequence is utilized for lysosomal ADC cleavage and release of active metabolites with an appropriate profile matching the KSPi mode of action.

9:40 NAMPT Inhibitors as a Novel Payload Class for Antibody-Drug Conjugates

Neumann_ChrisChris Neumann, PhD, Principal Scientist, Medicinal Chemistry, Seattle Genetics

ADC technology is limited by the diversity of chemical payloads that retain activity in this targeted delivery format. Our group has identified NAMPT inhibitors as an ADC-compatible drug class with a distinctive mechanism targeting cellular metabolism. We report the development of a hydrophilic, cleavable linker for NAMPT inhibitors that enables targeted delivery. The favorable activity and toxicity profiles of the ADCs in preclinical models demonstrates a promising advance in the field with potential clinical utility.

10:10 Coffee Break in the Exhibit Hall with Poster Viewing

10:15 Women in Science Speed Networking in the Exhibit Hall

10:55 Towards a Deeper Understanding of the Immune Modulatory Properties of Cytotoxic Antibody-Drug Conjugates

Bialucha_Carl_UliCarl Uli Bialucha, PhD, Director, Oncology Biotherapeutics, Novartis Institutes for Biomedical Research, Inc.

Antibody-drug conjugates (ADCs) are multi-component drugs that leverage several mechanisms of action including immune-modulation of the tumor microenvironment. Our investigations have focused on dissecting the role played by the antibody component vs. that of the payload and the specific molecular mechanisms that drive immune-modulation by anti-mitotic ADCs. Our data further our understanding of the complex pharmacodynamic changes induced by ADCs and highlight avenues for rational combination strategies.

11:25 Drug Conjugates Based on Engineered Affibody Molecules

Graslund_TorbjornTorbjörn Gräslund, PhD, Professor, Protein Science, KTH Royal Institute of Technology

Affibody molecules are small (58 aa), folded and robust non-Ig based affinity proteins. We have recently developed drug conjugates based on engineered affibody molecules with specific affinity for the HER2 receptor, coupled to the small molecule drug DM1. Affibody molecules allow for site-specific drug attachment and easy control over DAR. We found that the drug conjugates were potent agents for treatment of xenografted human tumors in mice.

11:55 Bispecific ADCs for Improved Tumor Targeting Specificity

Liu_DavidDavid V. Liu, PhD, Director, Protein Engineering, Abbvie

The combination of two specificities against targets co-expressed on cancer cells has the potential to improve specificity of targeting and increase the therapeutic index of antibody-drug conjugates. In this presentation, data will be presented on a 1+1 bispecific antibody-drug conjugate against two cancer stem cell associated targets. The discovery, in vitro screening and in vivo validation of this construct will be presented.

12:25 pm Computational Approaches for Optimizing the Developability of Biotherapeutics

Nels Thorsteinson, Scientific Services Manager, Biologics, Chemical Computing Group

mAb candidates identified from high-throughput screening or binding affinity optimization often present liabilities for developability, such as aggregation-prone regions or poor solution behavior. In this work, we optimized an integrin α11 binding mAb for developability using homology modeling and rational design where reducing hydrophobic surface patches improved HIC behavior. A retrospective data analysis demonstrates that 3D descriptors and multi-parameter models can screen candidates and enrich libraries with favorable developability properties for a range of biotherapeutics.

12:55 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:55 Session Break

ADCS TARGETING THE TUMOR MICROENVIRONMENT

2:10 Chairperson’s Remarks

Philipp Spycher, PhD, PSI Founder Fellow, Center for Radiopharmaceutical Sciences (CRS), Paul Scherrer Institute


2:15 KEYNOTE PRESENTATION: Using Matrix Protein Affinity to Modulate the Tumor Microenvironment

Hubbell_JeffreyJeffrey A. Hubbell, PhD, Eugene Bell Professor in Tissue Engineering, Institute of Molecular Engineering, University of Chicago

Cancer immunotherapy with immune checkpoint inhibitors (CPI) and interleukin (IL)-2 has demonstrated clinical efficacy but is frequently accompanied with severe adverse events caused by excessive and systemic immune system activation. Here, we addressed this need by targeting both the CPI antibodies αCTLA4 + αPD-L1 and the cytokine IL-2 to tumors via conjugation or recombinant fusion to a collagen-binding domain derived from the blood protein von Willebrand factor A3 domain, harnessing the exposure of tumor stroma collagen to blood components due to the leakiness of the tumor vasculature.

2:45 Overcoming Cancer Heterogeneity with Tumor Microenvironment-Targeted Antibody-Drug Conjugates

Neschadim_AntonAnton Neschadim, PhD, MBA, CEO, ImmunoBiochem Corporation

Solid tumors are evasive and heterogeneous, lacking surface tumor markers that are expressed consistently and abundantly. Unlike surface-based targets, levels of certain proteins in the cancer cell secretomes are selectively increased in the tumor microenvironment, but not normal environment. ImmunoBiochem is leveraging these targets for the selective delivery of highly-potent payloads directly to all cancer cells in the tumor, as well as various tumor-supporting cells, overcoming the challenges of heterogeneity, resistance and poor tumor penetration.

3:15 Sponsored Presentation (Opportunity Available)

3:45 Refreshment Break in the Exhibit Hall with Poster Viewing

4:45 Problem-Solving Breakout Discussions - Click here for details

5:45 Networking Reception in the Exhibit Hall with Poster Viewing

7:00 End of Day

THURSDAY, APRIL 11

8:00 am Registration and Morning Coffee

OPTIMIZING LINKERS AND CONJUGATION TECHNOLOGIES

8:30 Chairperson’s Remarks

Thomas Pillow, PhD, Senior Scientist, Discovery Chemistry, Genentech

8:35 Taming Random Conjugation: A General Approach for Equimolar Conjugation of Proteins and Payloads

Kolodych_SergiiSergii Kolodych, PhD, CSO, Syndivia

Multiple conjugation sites are usually available on a biomolecule. Upon conjugation, they produce a mixture of species having different degrees of conjugation (DoC). We report a general conjugation approach for achieving a defined DoC, which is virtually applicable to any biological macromolecule and payload. Applied to native antibodies, the method yields highly homogenous antibody-drug conjugates, antibody-oligonucleotide conjugates as well as bispecific scaffolds.

9:05 Disulfide Re-Bridging with Pyrrolobenzodiazepine Dimers Enable the Formation of Homogeneous, Potent and Differentiated Full-Length Antibody and Fab-Fragments Drug Conjugates

Dimasi_NazzarenoNazzareno Dimasi, PhD, Associate Director R&D, MedImmune

Homogeneous full-length antibodies and Fab-fragments pyrrolobenzodiazepine conjugates with a drug to antibody ratio of one are presented. These ADCs are prepared using dual-maleimide pyrrolobenzodiazepine dimers that have been engineered to re-bridge two adjacent cysteines at the antibody hinge, at an engineered position in the CH2 domain and at the Fab cysteines forming the intrachain disulfide bond.

9:35 Sponsored Presentation (Opportunity Available)

10:05 Coffee Break in the Exhibit Hall with Poster Viewing

11:05 Site-Selective, Serum Stable ADCs Using Next-Generation Maleimide Linkers

Baker_JamesJames Baker, PhD, Associate Professor, Chemistry, University College London

This talk will describe the development and application of the next-generation maleimide class of reagents for the construction of ADCs. It will include a discussion of optimized dibromomaleimide and monobromomaleimide platforms for the rapid formation of robustly stable ADCs, by either rebridging the native disulfide bonds or conjugating to ThiomabsTM respectively. Insights into the application of these approaches for the construction of multispecifics will also be made, along with new enabling conjugation platforms.

11:35 Straightforward Site-Specific Payload Attachment to Native Antibodies without Antibody Engineering

Spycher_PhilippPhilipp Spycher, PhD, PSI Founder Fellow, Center for Radiopharmaceutical Sciences (CRS), Paul Scherrer Institute

We will introduce a new antibody-conjugation technology that enables site-specific payload attachment to native antibodies without engineering. Using this approach, well-defined ADCs can be generated directly from antibodies ‘off-the-shelf’ within less than two days and that have a drug-to-antibody ratio (DAR) of 2. We will provide a comprehensive set of data demonstrating that the ADCs generated with our new technology retain their binding properties, are highly cytotoxic to target over-expressing cell-lines and are stable with no drug-loss over extended periods.

12:05 pm ALT-P7: Development of HER-2 Targeting ADC for Treatment of Breast/Gastric Cancer by Use of Site-Specific Conjugation (Nexmab) Technology

Lee_SunbaeSunbae Lee, PhD, Senior Research Scientist, Alteogen

In NexMab conjugation technology, metal-ion binding peptide motif is introduced at the C-terminus of antibody heavy chain for the site-specific conjugation of payload. This talk will present the high structural stability and in intro/vivo efficacy of HER-2 targeting ADC, constructed by NexMab conjugation method with DAR 2.

12:35 End of Engineering Antibody-Drug Conjugates


Recommended Short Course*

SC12: Design Strategies and Development of ADCs

Robert Lutz, PhD, Principal Consultant, Crescendo Biopharma Consulting

 

*Separate registration required.

* The program is subject to change without notice, due to unforeseen reason.

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Update History
2019/02/15
Sponsor updated
2019/02/05
Agenda,Speaker,Sponsor updated
2019/01/09
Sponsor updated


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