Antibody-based immunotherapy is a promising strategy in cancer treatment. IgG eliminates tumor cells through NK cell-mediated ADCC and macrophage-mediated antibody-dependent phagocytosis. Neutrophils have been largely overlooked as potential effector cells because IgG ineffectively recruits neutrophils. Bispecific antibodies, which potently activate neutrophils and induce migration through FcaRI (CD89), have been developed. Coupling of TNFa activates neutrophils as effector cells, which will be discussed.

T cell in the tumor microenvironment requires TCR engagement, co-stimulation, and cytokines to promote activation, differentiation, and proliferation. Tumor cells lack expression of the ligands necessary to promote robust T cells activity with existing immune therapies. This presentation will describe preclinical data on combinations of CD28 co-stimulation, checkpoint blockade, and T cell redirecting bispecifics to enhance anti-tumor efficacy of immune-oncology therapies. Data will be presented on engineering criteria for cell-based assays with different TCR engagement modalities to describe the function of bi/trispecifics for treatment of solid tumors.

This presentation will describe pre-clinical data from Regeneron’s new clinical approaches to enhancing anti-tumor efficacy of T cells, focusing on the combination of costimulatory bispecific antibodies with checkpoint blockade and T cell redirecting bispecifics. In addition, data from new classes of T cell targeted enhancement strategies in preclinical development will be discussed.

Our team has developed a technology to enable the development of site-specific bioconjugates made with novel linkers that are stable in the circulation. The improved efficacy and tolerability made possible by these optimized conjugates widens the therapeutic window and shows the potential for improved therapeutic treatment options.

When does a new platform transition from innovation to derivation? The purpose of this presentation is to speak to other oncology “bubbles” where multiple competitors enter the field. With venture capital funding tight right now is there a flaw in defaulting to known targets and payloads which have a lower likelihood of transformative or commercial success. Using historical examples, the goal of this presentation is to ensure ADCs remain innovative and continue to advance the field while avoiding the traps of the past

Amatoxin-based ADCs (ATACs) differ from other ADCs through the use of the RNA-polymerase II inhibitor amanitin as toxic payload. Amanitin is a hydrophilic and thus biophysically unique payload. In consequence, ATACs have a distinct off-target toxicity profile compared to other approved ADCs. This can be reduced by sequence optimization of the antibody moiety. Additionally, changing the route of administration refines PK parameters leading to an improved therapeutic index.  

Bispecific antibodies can manifest into higher specificity and stronger potency. Combination with standards of care molecules can enhance potency and efficacy. 

Intracellular oncoproteins are potentially attractive targets for antibody therapy, as their mutation-containing fragments can be presented by MHC as tumor-specific neoantigens. However, recognizing minimal differences between oncomutations and their normal counterparts is challenging. We have developed the HapImmune technology that exploits hapten-peptide conjugates generated by small-molecule covalent inhibitors as distinct neoantigens presented on MHC to enable engineered antibodies to selectively kill drug-resistant cancer cells.

Indications for the use of antibody–drug conjugates (ADCs) are rapidly expanding, with development progressively moving from the advanced-stage to the early-stage setting, and from monotherapy to combination strategies. Despite being designed with the rationale of expanding the therapeutic indices of conventional chemotherapies, most ADCs have a toxicity profile similar to that of their cytotoxic payload. Unconventional and potentially life-threatening toxicities can also be observed with certain ADCs, requiring an increased understanding of these events and the optimization of diagnostic and management practices. This talk will review the multiple strategies being pursued to optimize the safety of ADCs. 

CAR T and anti-CD47 therapy are two distinct immunotherapies that we found to be non-compatible in combination due to depletion of adoptively transferred T cells by macrophages. We engineered CD47 for selective binding to be insensitive to CD47 therapy and demonstrated that the combination of CAR T cells expressing engineered CD47 and CD47 blockade results in synergistic control of multiple solid tumors by harnessing T cell and macrophage antitumor activity.

Bispecifics, ADCs, and combinations have revolutionized cancer treatment and the suffering of cancer patients. The presentation will include three key updates in the field: advances in bispecific and ADCs (including efficacy and safety), mitigation strategies to improve the efficacy and reduce toxicity (of these, two key therapeutics will be discussed), and combination strategies for specifics, targeted therapies, chemo, and ADCs.

Bispecific antibody drug conjugates (bsADCs) are emerging as a new, promising modality that may provide improved efficacy and safety in cancer therapy. Biocytogen’s RenLite fully human, common light chain antibody platform allows rapid construction of bispecific antibodies of choice targeting a wide variety of tumor-associated antigens. The presentation will highlight Biocytogen’s bsADC programs that demonstrate the enhanced anti-cancer activities of bsADCs in preclinical models.

AZD9592 is a first-in-class bispecific ADC designed to target EGFR and cMET, independent of pathway-mediated resistance mechanisms that limit other targeted agents. The ADC was constructed on the backbone of the DuetMab monovalent bispecific IgG platform and was engineered with higher affinity for cMET compared to EGFR (>15 fold), with the aim of reducing EGFR-driven toxicity in normal tissues. The antibody is conjugated via a cleavable linker to a topoisomerase 1 inhibitor (TOP1i) payload (AZ14170132). AZD9592 is active in PDX models representing a broad clinical line of sight and shows a promising safety profile in cynomolgus monkeys.