Bispecific antibodies continue to show significant and impressive therapeutic value. While the development of bispecific antibodies is an evolving field, many challenges are still awaiting to be solved by experts in the field including target selection, better understanding of their mechanism of action, along with the combination selection of targets. CHI’s Second Annual Bispecific Antibody Design conference will delve directly into the technical challenges of bispecific development to improve your candidates’ translatability into the clinic.

Final Agenda

MONDAY, AUGUST 19

11:30 am Short Course Registration

12:00 – 3:00 pm SC1: The Making of Bispecific Antibodies

3:30 – 6:30 pm SC2: Developability and Manufacturing Considerations for Bispecific Antibodies

*Separate registration required.

TUESDAY, AUGUST 20

7:45 am Registration & Morning Coffee

OPENING KEYNOTE SESSION

8:30 Chairperson’s Opening Remarks

Roland E. Kontermann, PhD, Professor, Institute of Cell Biology and Immunology, Stuttgart Research Center Systems Biology, University of Stuttgart

8:35 Advances in Immunotherapy: Maximizing T cell Responses with Tumor Antigen Directed Bispecific Antibodies and Co-Stimulation

Maria Karasarides, PhD, Executive Director, ImmunoOncology, Regeneron Pharmaceuticals

Immunotherapy has advanced as an integral cancer treatment modality primarily from the survival outcomes observed from checkpoint inhibition (α-CTLA-4, α-PD-1,α-PD-L1). While the benefits from checkpoint inhibition are evident, long term survival is enjoyed by only a small proportion of cancer patients harboring immune-responsive tumors. In this talk we will (1) review the long term survival outcomes provided by checkpoint inhibition (2) discuss immunotherapy combination strategies and outcomes to date (3) explore potential of achieving maximal T cell responses through the use of tumor antigen directed bispecific antibodies and co-stimulation to address the unmet need remaining for cancer patients with immune-response and non-responsive tumors.

9:05 Unveiling the Strength of Alternative Scaffolds

H. Kaspar Binz, PhD, CEO & Founder, Binz Biotech Consulting

Alternative scaffolds promise the creation of novel biologics with potential beyond that of classical monoclonal antibodies. With safety doubts dispelled with clinical data, we now start to see the technologies to unfold their key strengths. This overview includes a review on key milestones achieved during the establishment of alternative scaffolds, a status quo analysis, as well as an outlook of where the field is heading.

9:35 TriKE-Based Combinatorial Therapy for Pancreatic Ductal Adenocarcinoma

Soldano Ferrone, MD, PhD, Professor in Residence, Surgical Oncology, Surgery, Massachusetts General Hospital, Harvard Medical School

I will describe the use of TriKEs as an effector mechanism for immunotherapy. In these constructs IL-15 has been added to the conventional bispecific NK Cell immune engagers (BiKEs) platform and used to crosslink the scFv fragments derived from the B7-H3-specific mAb 376.96 to a highly modified camelid CD16 (FCγRIII)-specific scFv fragment. The latter binds to NK cells, while the former to PDAC cells. Strategies to enhance the activity of TriKEs will be discussed.

10:05 Networking Coffee Break

ENGINEERING INNOVATIONS FOR BI- AND MULTI-SPECIFIC PLATFORMS

10:35 Chairperson’s Remarks

Diego Ellerman, PhD, Principal Scientific Researcher, Genentech

10:40 Bi-Specific Antibodies - Platform Approaches to Rapidly Generate Binder – and Format Variability and New Functionalities

Ulrich Brinkmann, PhD, Expert Scientist, Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, FRG

I will be discussing three key points in this talk: (1) Platform technology to rapidly generate many binder-format combinations; (2) Format matters – combinations of suitable binders and formats generate the ‘best’ bsAbs; and (3) New formats – new applications – new functionalities.

11:10 Concept to Clinic: Development of Fc-Containing XmAb® Bispecific Antibodies for Immunotherapy

Umesh S. Muchhal, PhD, Director, Protein Sciences, Xencor, Inc.

We present a robust heterodimeric Fc platform, called the XmAb bispecific platform, engineered for efficient development of bispecific antibodies and Fc fusions of multiple formats. First, we engineer a purification solution for proteins containing a heterodimeric Fc using engineered isoelectric point differences in the Fc region that enable straightforward purification of the heterodimeric species. Then, we combine this purification solution with a novel set of Fc substitutions capable of achieving heterodimer yields over 95% with little change in thermostability. Next, we illustrate the flexibility of our heterodimeric Fc with a case study in which a wide range of tumor-associated antigen × CD3 bispecifics are generated, differing in choice of tumor antigen, affinities for both tumor antigen and CD3, and tumor antigen valency. Finally, we present manufacturing data reinforcing the robustness of the heterodimeric Fc platform at scale.

11:40 Design and Development of Innovative Bispecific Antibodies

Lan Tang, Technical Account Manager,  BDBU,  GenScript

Major challenges in bispecific antibody development are developability and manufacturing. GenScript proprietary SMAB (single-domain antibody fused to monoclonal antibody) bispecific antibody platform minimizes the immunogenicity and manufacture concerns of current bispecific antibody platforms while enabling bi-valent and multi-valent therapeutics. 

12:10 pm Luncheon Presentation: Development and Application of Innovative Immuno-Oncology Mouse Models

Cunxiang Ju, Research & Development Director,  R&D department,  Gempharmatach.Co.,Ltd

Mouse is the most common used animal model in preclinical evaluation of new drugs. However，due to the species barrier，there is neither human targets nor human immune cells, mice cannot be directly used for pre-clinicalstudy of macromolecular drugs such as antibodies.Fortunately, genetic modified mouse model (GEMM) created by gene editing can solve this issue. In vitro and in vivo studies of CD3 based bi-specific antibodies can be effectively evaluated with CD3 humanized BALB/c mouse.

12:40 Session Break

1:30 A Novel Platform for the Generation of Multivalent and Multispecific Ig-Like Molecules

Oliver Seifert, PhD, Senior Scientist, Institute of Cell Biology and Immunology, University of Stuttgart

The talk presents data on a novel platform allowing generation of molecules of varying specificity and valency, designated diabody-Ig (Db-Ig). The antigen-binding site of Db-Ig is composed of a diabody in the VH-VL orientation stabilized by fusion to antibody-derived homo- or heterodimerization domains, e.g. CH1/CL or the heavy chain domain 2 of IgE (EHD2) or IgM (MHD2), further fused to an Fc region. Exemplary bispecific molecules will provide proof on concept.

2:00 Multispecific Antibody Development Platform Based on Human Heavy Chain Antibodies

Omid Vafa, PhD, MBA, Chief Business Officer, Teneobio, Inc.

Here, we present an innovative platform for generating fully human heavy chain-only antibodies that have been matured in vivo. Our unique approach combines antibody repertoire analysis with immunization of humanized transgenic rats (UniRats) that produce human HCAbs (UniAbs) in response to antigen challenge. UniRats express UniAbs from large transgenes representing the full human heavy chain V(D)J repertoire, mount robust immune responses to a wide variety of antigens, exhibit diverse V gene usage and generate antigen-specific antibodies with a wide range of characteristics. We demonstrate the capabilities of this platform, including the ability to accelerate the development of next generation bi- and multi-specific antibody therapeutics.

2:30 Networking Refreshment Break

3:00 Engineering Anticalin-Based Bispecifics to Leverage Its Format Flexibility in Immuno-Oncology

Stefan Grüner, PhD, Scientist, Molecular Biology and Protein Engineering, Pieris Pharmaceuticals

Anticalin-based bispecifics are clinically tested biologics containing Anticalin proteins derived from highly stable human protein scaffolds. We will show that the format flexibility of Anticalin proteins can be leveraged to rapidly generate bispecifics with distinct activity profiles. We also present case studies in which rational protein engineering of Anticalin-based bispecifics was used to specifically tune their properties.

3:30 Tetravalent Biepitopic Targeting Enables Intrinsic Antibody Agonism of TNFRSF Members

Yanli Yang, PhD, Senior Scientific Researcher, Antibody Engineering Department, Genentech

Agonism of members of the TNF Receptor Superfamily (TNFRSF) with monoclonal antibodies are of high therapeutic interest due to their role in immune regulation and cell proliferation. A major hurdle for pharmacologic activation of this receptor class is the requirement for high-order clustering, a mechanism that imposes a reliance in vivo on Fc receptor-mediated crosslinking. This extrinsic dependence represents a potential limitation of virtually the entire pipeline of agonist TNFRSF antibody drugs, of which none have thus far been approved or reached late stage clinical trials. We show that tetravalent biepitopic targeting enables robust intrinsic antibody agonism for two members of this family, OX40 and DR5, that is superior to extrinsically crosslinked native parental antibodies. Tetravalent biepitopic anti-OX40 engagement co-stimulated OX40low cells, obviated the requirement for CD28 co-signal for T cell activation, and enabled superior pharmacodynamic activity relative to native IgG in a murine vaccination model. This work establishes a proof-of-concept for an engineering approach that addresses a major gap for the therapeutic activation of this important receptor class.

4:00 Problem Solving Roundtable Discussions

Novel Scaffolds as Multi-Functional Drugs

Moderator: H. Kaspar Binz, PhD, CEO Binz Biotech Consulting

• What are the opportunities for using non-immunoglobulin binding domains?
• What challenges would one expect for novel scaffolds?
• Which benefits are expected when using novel scaffolds?
• Which approaches are enabled by novel scaffolds and which ones remain impossible?

Antibody Derivatives with Prodrug Functionality

Moderator: Ulrich Brinkmann, PhD, Expert Scientist, Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, FRG

• Academic/exotic playground vs next generation platforms?
• What for alternatives?
• Pro/con of different in/activation approaches?

5:00 Welcome Reception in the Exhibit Hall with Poster Viewing

6:00 End of Day

WEDNESDAY, AUGUST 21

8:00 am Registration & Morning Coffee

T-CELL ENGAGERS

8:30 Chairperson’s Remarks

G. Jonah Rainey, PhD, Vice President, Antibody Therapeutics, Gritstone Oncology

8:35 A Novel T-Cell Engaging Bispecific Antibody Platform: Maximizing Tumor Cell Lysis While Minimizing Cytokine Toxicity and T-Cell Exhaustion

Nathan Trinklein, PhD, Chief Technology Officer, Discovery Research, Teneobio

Using a unique sequence-based discovery approach along with proprietary transgenic rats, we have created a large collection of fully human anti-CD3 antibodies with diverse T-cell agonist activities. The CD3 antibodies identified by our platform show diverse in vitro T-cell activation profiles measured by CD69 upregulation, IL2, and IFNg production. We also generated human domain antibodies targeting a variety of tumor antigens that we combined with our unique CD3 antibodies to create bispecific molecules that mediate redirected T-cell killing of tumor cells. In one particular example, we have created a panel of aCD3:aBCMA bispecific antibodies for the treatment of multiple myeloma that stimulate different levels of T-cell activity. Using a multiple myeloma tumor cell line along with primary human PBMCs, we demonstrate a spectrum of in vitro tumor cell killing activity with varied levels of cytokine release using our bispecific molecules with diverse CD3 binding activities. In summary, we have created a T-cell engaging bispecific antibody platform with tuned T-cell agonism that can be used to optimize the therapeutic index for a variety of tumor antigens.

9:05 Factors Influencing Potency and Tumor Selectivity of T-Cell Engaging Bispecific Abs

Diego Ellerman, PhD, Principal Scientific Researcher, Genentech

T-cell redirected cytotoxicity has become a major modality in modern biotherapeutics. Both their potency and tumor selectivity are properties important for an efficacious and safe clinical use. This talk will analyze different factors related to the antigen as well as the bispecific Ab that influence the potency as well as emerging strategies to make T-cell engagers more tumor-selective.

9:35 Enhancing Safety and Efficacy for Bispecific T-Cell Engager (BiTE®) Antibody

Tara Arvedson, PhD, Director, Oncology Research, Amgen

Bispecific T-cell engagers (BiTEs) are a new class of immunotherapeutic molecules intended for the treatment of cancer. These molecules enhance the patient's immune response to tumors by retargeting T-cells to tumor cells. BiTEs are constructed of two single-chain variable fragments (scFv) connected in tandem by a flexible linker. One scFv binds to a T-cell-specific molecule, usually CD3, whereas the second scFv binds to a tumor-associated antigen. This structure and specificity allow a BiTE to physically link a T-cell to a tumor cell, ultimately stimulating T-cell activation, tumor killing and cytokine production. BiTEs have been developed, which target several tumor-associated antigens, for a variety of both hematological and solid tumors. Several BiTEs are currently in clinical trials for their therapeutic efficacy and safety. This talk examines the salient structural and functional features of BiTEs, as well as the current state of their clinical and preclinical development.

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

10:45 How We Approached the Clinical Development of CD20-TCB, a Novel 2:1 Format T-Cell Engaging Bispecific Antibody

Tom Moore, PhD, Project Team Leader, Early Development, Roche

CD20-TCB is a novel 2:1 format T-cell-engaging bispecific antibody which already at suboptimal doses displays promising clinical activity in heavily-pretreated B-NHL. In addition, Gpt has shown clinical proof of principle as an approach to efficiently mitigate CRS. An update on safety and efficacy as well as biomarker data will be presented.

11:15 PANEL DISCUSSION: Challenges and Opportunities of T-Cell Engagers

Moderator: G. Jonah Rainey, PhD, Vice President, Antibody Therapeutics, Gritstone Oncology

Panelists: All Speakers in the Session

• Current challenges and opportunities of developing T-cell engagers
• CD3/TCR aspects in safety, dose management, and efficacy
• Ways to mitigate toxicity

12:15 pm Luncheon Presentation: A Donor Dependent In Vivo Model for Checkpoint and Bispecific Antibody Related Cytokine Release Syndrome Safety Evaluation

James Keck, PhD,  Senior Director, Innovation and Product Development, The Jackson Laboratory

Monoclonal antibodies (mAbs) have shown remarkable efficacy as a cancer immunotherapy treatment.  Unfortunately, patients treated with mAbs can develop severe adverse effects, including cytokine release syndrome (CRS), which cannot be reliably detected by either in vitro assays with human PBMCs or in vivo testing in animal models. We have developed a rapid, sensitive, and reproducible PBMC humanized mouse model for quantitating checkpoint and bispecific inhibitor treatments related CRS.  Data utilizing these therapeutics will be presented.  

12:45 End of Bispecific Antibody Design