The recent approval of Pfizer’s Besponsa® ADC for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) not only brings hope to ALL patients, but is also a boon to the industry’s confidence in ADC technologies. As of May 2017, there are 70 ADCs in the clinic at various stages of clinical trials. In addition to ADC monotherapies, combination therapies are also on the rise, including ADC/Immuno-Oncology and bispecific/ADC combinations.

CHI’s Clinical Progress of Antibody-Drug Conjugates will present updates on ADCs currently in the clinic, showcase the current and future state of ADC-IO combinations, highlight some exciting pre-clinical results as well as assess the PKPD challenges.

Final Agenda

THURSDAY, MAY 3

ADC-IO COMBINATIONS
Harborview 1&2

12:00 pm Registration (Commonwealth Hall)

12:35 Luncheon in the Exhibit Hall with Poster Viewing (Commonwealth Hall)

1:40 Chairperson’s Remarks

Gail Lewis Phillips, MSc, Senior Scientist, Translational Oncology, Genentech, Inc.

1:50 The Past, Present and Future of ADC-IO Combinations

Jay Harper, PhD, Senior Scientist, Oncology Research, MedImmune

Exciting preclinical data demonstrated immunomodulatory effects of antibody-drug conjugate (ADC) warheads and synergistic anti-tumor activity when ADCs are combined with immuno-oncology agents, leading to clinical development of such strategies. This presentation will highlight the key data supporting such ADC-IO combinations, provide an overview of the current ADC-IO clinical landscape, and will provide some insight into the next generation of these promising ADC-IO combinations.

2:20 Clinical Learnings from Mirvetuximab Soravtansine (IMGN853) and Pembrolizumab Combination Therapy

Eric Westin, PhD, VP, Clinical Development, ImmunoGen

2:50 Combination of Antibody-Cytokine Fusions with Immunological Check-Point Inhibitors

Alessandra Micaela Villa, PhD, Head, Phage Display Technologies, Philochem AG

Antibody-cytokine fusion proteins (“immunocytokines”) represent a novel class of antibody therapeutics that combine the disease-homing property of antibodies with the immunomodulatory activity of cytokine payloads. Immunocytokines are currently being developed for the treatment of cancer and other serious conditions. I will present preclinical and clinical data on the combination of immunocytokines with other therapeutic treatments, including immunological checkpoint inhibitors.

 3:20 Regulatory Considerations in the IND Submission of Antibody and Related Products

Audrey Jia, PhD, Former FDA CMC Senior Reviewer for Biological Products , Datarevive, Sponsored by MabPlex

This short presentation will discuss the general requirement for US IND applications, including the considerations in CMC, nonclinical and clinical perspective. Common questions regarding the IND application will be discussed for different clinical phases.

3:35 Sponsored Presentation (Opportunity Available)

3:50 Networking Refreshment Break (Harbor & Mezzanine Level)

CLINICAL advances
Harborview 1&2

4:20 Antibody-Pyrrolobenzodiazepine Conjugates

Philip Howard, PhD, CSO, Spirogen; Senior Fellow, MedImmune

This talk will cover the development of Pyrrolobenzodiazepine (PBD) payloads for use in Antibody Conjugates. The presentation will also give an update on the clinical progress of Antibody PBD Conjugates.

4:50 Trop-2 as a Broad Solid Cancer Target for Antibody-Drug Conjugates

David Goldenberg, ScD, MD, Founder and Former CSO, Immunomedics, Inc.

Trop-2 is a transmembrane glycoprotein that transduce cytoplasmic calcium signal, activates MAPK/ERK pathway, and affects cell-cell adhesion. Using a proprietary linker technology to site-specifically conjugate an average of 7.6 molecules of SN-38 (the active metabolite of irinotecan, which inhibits nuclear topoisomerase I) per humanized IgG, my group demonstrated effective and selective tumor inhibition in vitro and in xenograft solid tumor models, as well as in phase 2 studies of ~500 patients with advanced, heavily-pretreated diverse solid cancers (e.g., breast, NSCLC, SCLC, urothelial).

5:20 End of Day

5:20 Registration for Dinner Short Courses (Commonwealth Hall)

Recommended Short Course(s)*

SC10: Critical Considerations for the Design and Development of Antibody-Drug Conjugates

*Separate registration required.

FRIDAY, MAY 4

8:00 am Morning Coffee (Harbor Level Lobby)

CLINICAL advances (CONT.)
Harborview 1&2

8:30 Chairperson’s Remarks

Philip Howard, PhD, CSO, Spirogen; Senior Fellow, MedImmune

8:35 KEYNOTE PRESENTATION: Early Clinical Development of Dolaflexin ADCs

Timothy B. Lowinger, PhD, CSO, Mersana Therapeutics

XMT-1522 is a HER2-targeting ADC that induces complete regressions in models of treatment-resistant HER2-positive breast and gastric tumors, as well as breast and non-small cell lung cancer (NSCLC) without HER2 gene amplification and lower levels of HER2 expression. XMT-1536 is a Dolaflexin ADC targeting NaPi2b that is highly active in models of NSCLC adenocarcinoma and epithelial ovarian cancer. Both XMT-1522 and XMT-1536 are in Phase 1 clinical development in patients with advanced solid tumors.

9:05 ABBV-399, a Clinical Antibody Drug Conjugate that Targets c-Met Overexpressing Solid Tumors

Ed Reilly, PhD, Senior Research Fellow, Project Director, Oncology Discovery, AbbVie

ABBV-399 (Teliso-V) is a novel first-in-class ADC comprised of the c-Met-targeting antibody ABT-700 conjugated to the cytotoxic MMAE. ABBV-399-mediated killing requires a threshold level of c-Met expressed by many tumors thereby reducing both the binding of ABBV-399 to normal tissues and the risk of on-target toxicity. ABBV-399 has progressed to a Phase 1 study where it has been well tolerated and has produced objective responses in c-Met-expressing non-small cell lung cancer (NSCLC) patients both as monotherapy and in combination. A summary of these clinical results will be presented.

9:35 Poster Highlight: The Journey of Mylotarg (TM) from Discovery to Regulatory Approval

Durgesh V Nadkarni, PhD, Senior Principal Scientist, Bioprocess R&D, Pfizer Inc.

Mylotarg(TM) (gemtuzumab ozogamicin) is an antibody-drug conjugate (ADC) indicated for the treatment of acute myeloid leukemia (AML). The ADC is composed of an anti-CD33 humanized IgG4 mAb that is covalently conjugated to a toxic small moleculr payload, N-acetyl-gamma-calicheamicin via a hydrazone linker. The linker-payload and ADC were first designed and synthesized in the early 1990s. This poster presents a historical account of the development of Mylotarg from early discovery through regulatory approval.

10:05 Networking Coffee Break (Harbor & Mezzanine Level)

PRECLINICAL UPDATES
Harborview 1&2  

10:35 Novel Strategies for Developing 2nd Generation HER2-Directed Antibody-Drug Conjugates

Gail Lewis Phillips, MSc, Senior Scientist, Translational Oncology, Genentech, Inc.

Trastuzumab emtansine (T-DM1) is a HER2-directed ADC comprised of trastuzumab linked to the anti-mitotic agent, DM1, through a stable linker. We have designed a different HER2 ADC using a unique THIOMAB™ antibody with engineered cysteines for enhanced stability. To differentiate from T-DM1, we assessed numerous DNA-damaging drugs with cleavable and uncleavable linkers. Preclinical data will be presented for a 2nd generation HER2-ADC comprised of a disulfide-linked DNA damaging agent.

11:05 Preclinical Evaluation of a GCC-Targeted Antibody-Drug Conjugate (ADC) for the Treatment of Colorectal Cancers and Other GI Malignancies

Adnan Abu-Yousif, PhD, Senior Scientist II, Discovery, Takeda

Guanylyl cyclase C (GCC) is a transmembrane cell surface receptor that functions in the maintenance of intestinal fluid, electrolyte homeostasis, and restriction of cell proliferation. In normal human tissues, GCC expression is restricted to the mucosal cells lining the GI tract. Here we describe the activity of a GCC-targeted antibody drug conjugate in preclinical models of GCC-positive tumors. These promising preclinical data warrant advancement of this ADC to clinical evaluation.

11:35 Tackling Solid Tumours with Antibody Fragment Drug Conjugates (FDCs)

Mahendra Deonarain, PhD, CEO & CSO, Antikor Biopharma Ltd.

The significant majority of the ADC field are focusing on large, engineered IgG with low DAR but we believe that FDCs represent a major opportunity to treat solid tumours. We can engineer antibody fragments to carry a high quantity of cytotoxic payload, that will penetrate tumours rapidly, deliver the killer blow and clear from the circulation quickly resulting in lower adverse effects. We will present compelling efficacy and tolerability data to support the concept.

12:05 pm AbGn-107, an ADC Targeting Gastrointestinal Tumors 

David (Shih-Yao) Lin, MD, PhD, CMO, AbGenomics International

AbGn-107 is an ADC recognizing a glycol-epitope specifically expressed in GI tumors, especially pancreatic, gastric, colorectal and biliary tumors. The research and clinical development of AbGn-107 will be covered by this presentation.

12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on your Own

1:05 Networking Refreshment Break (Harbor & Mezzanine Level)

PKPD ASSESSMENT AND MODELING
Harborview 1&2

1:35 Chairperson’s Remarks

Pamela Trail, Independent Consultant and Former Vice President, Oncology, Regeneron

1:40 Biomarkers of the Mononuclear Phagocytic System (MPS) for the Pharmacokinetics and Pharmacodynamics of the Antibodies and Antibody Drug Conjugates

William C. Zamboni, PharmD, PhD, Associate Professor and Director, Translational Oncology and Nanoparticle Drug Development Initiative (TOND2I) Laboratory, UNC Lineberger Comprehensive Cancer Center

The factors affecting the high pharmacokinetic (PK) and pharmacodynamic (PD) variability of antibodies (mAbs) and antibody drug conjugates (ADCs) are consistent with variability in the mononuclear phagocyte system (MPS). The high variability in MPS Fc-gamma-receptors (FcɣRs) and function in blood are associated with the high PK and PD variability of mAbs and ADCs. The high PK variability of these agents is clinically important as they have a narrow therapeutic index.

2:10 Will Optimized Single Molecular ADC Species Set New Precedents for Clinical Performance?

Trevor J. Hallam, PhD, CSO, Sutro Biopharma

We demonstrate a cell-free antibody production system that enables the use of reactive non-natural amino acids to generate precisely positioned irreversible conjugates with high fidelity. We are able to rapidly generate many variants of full length IgG species with different conjugation sites within days at quantities and quality sufficient for pharmacodynamic and toxicological assessment allows iterative design to optimize ADC performance and reduces preclinical development times by 18 months. We’ll provide updates on our lead clinical development candidates.

2:40 Translational Aspects of Auristatin-Based ADCs

Matthew Onsum, PhD, Director, Translational Sciences, Seattle Genetics

This presentation will assess the target expression and other patient characteristics vs. response; discuss dosing considerations and also explore pharmacodynamic and mechanism-of-action biomarkers supporting immuno-oncology combinations.

3:10 Harnessing Multiscale Modelling to Optimize Design of Antibody Drug Conjugates for Clinical Success

Renu Singh Dhanikula, PhD, Senior Research Investigator, MAP, Bristol-Myers Squibb Company

Mechanistic physiologically-based pharmacokinetic models (PBPK) can be used as a platform to study the impact of various ADC characteristics on their disposition in plasma, tissues and tumor, allowing us to build quantitative relationship between exposure and efficacy. The presentation will showcase how mathematical simulations can provide an efficient method for exploring the vast permutation and combinations of parameters influencing efficacy and toxicity of these complex molecules enabling selection of ADCs with an increased likelihood of success.

3:40 End of Conference